WO2022093981A1

WO2022093981A1 - Combination therapy comprising ptpn22 inhibitors and pd-l1 binding antagonists

Info

Publication number: WO2022093981A1
Application number: PCT/US2021/056883
Authority: WO
Inventors: Andrew C. Chan
Original assignee: Genentech, Inc.
Priority date: 2020-10-28
Filing date: 2021-10-27
Publication date: 2022-05-05

Abstract

The present disclosure provides methods of treating or preventing progression of cancer in an individual, increasing intratumoral CD8+ T cells in an individual with cancer, predicting immune- related adverse events in an individual with cancer, and predicting prognosis of treating an individual having cancer with a PD-1 axis binding antagonist. In some embodiments, the methods comprise administering to the individual an effective amount of a PTPN22 inhibitor and a PD-L1 binding antagonist or a PD-1 binding antagonist. In some embodiments, the methods comprise determining that the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide.

Description

COMBINATION THERAPY COMPRISING PTPN22 INHIBITORS AND PD-L1 BINDING ANTAGONISTS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. Provisional Application No.63/106,826, filed October 28, 2020, which is hereby incorporated by reference in its entirety. SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE [0002] The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 146392050940SEQLIST.TXT, date recorded: October 22, 2021, size: 32,412 bytes). FIELD [0003] The present disclosure relates to methods of treating or preventing progression of cancer in an individual, increasing intratumoral CD8+ T cells in an individual with cancer, predicting immune- related adverse events in an individual with cancer, and predicting prognosis of treating an individual having cancer with a PD-1 axis binding antagonist. In some embodiments, the methods comprise administering to the individual an effective amount of a PTPN22 inhibitor and a PD-L1 binding antagonist or a PD-1 binding antagonist. BACKGROUND [0004] Protein tyrosine phosphatase non-receptor type 22, or PTPN22 (also known as LYP in humans and PEP in mice), is a PTPase preferentially expressed in immune cells (R. J. Matthews, D. B. Bowne, E. Flores, M. L. Thomas, Mol. Cell. Biol.12, 2396–2405 (1992); S. Cohen, H. Dadi, E. Shaoul, N. Sharfe, C. M. Roifman, Blood.93, 2013–2024 (1999)) reviewed in T. Vang et al., Annu. Rev. Immunol.26, 29–55 (2008). It has been previously demonstrated that PTPN22 plays an inhibitory role in TCR activation of antigen-experienced T cells and in IFNAR signaling (K. Hasegawa, F. Martin, G. Huang, Science (80-. ).685, 685–690 (2009); D. A. Holmes et al., J. Exp. Med.212, 1081–1093 (2015); J. Zhang et al., Nat. Genet.43, 902–907 (2011); X. Dai et al., J. Clin. Invest.123, 2024–2036 (2013)). PTPN22 also plays inhibitory and activating roles in a number of additional innate and adaptive immune pathways including B-cell receptor (BCR) signaling and repertoire selection, Dectin-1 signaling in dendritic cells, toll-like receptor-, NOD2- and NLRP3- mediated functions in macrophages, Treg-development, adhesion and function, neutrophil adherence, and IgE receptor signaling in mast cells (M. Rieck et al., J. Immunol.179, 4704–4710 (2007); A. F. Arechiga et al., J. Immunol.182, 3343–3347 (2009); Y. Wang et al., Immunity.39, 111–122 (2013); D. D. Obiri et al., Allergy Eur. J. Allergy Clin. Immunol.67, 175–182 (2012); L. Menard et al., J. Clin. Invest.121, 3635–3644 (2011); H. A. Purvis et al., Front. Immunol.11, 1–12 (2020); H. A. Purvis et al., Eur. J. Immunol.48, 306–315 (2018); M. R. Spalinger et al., PLoS One.8 (2013), doi:10.1371/journal.pone.0072384; C. J. Maine et al., J. Immunol.188, 5267–5275 (2012); R. J. Brownlie et al., Sci. Signal.5, 1–12 (2012); S. Vermeren et al., J. Immunol.197, 4771–4779 (2016); M. R. Spalinger et al., Autophagy.13, 1590–1601 (2017)). [0005] A single-nucleotide polymorphism (SNP) transition in Ptpn22(C1858T) resulting in an arginine to tryptophan amino acid substitution at position 620 (R620W) is associated with the development of a variety of autoimmune disorders including rheumatoid arthritis, type 1 diabetes mellitus and systemic lupus erythematosus (SLE) amongst others (N. Bottini et al., Nat. Genet.36, 337–338 (2004); T. Mustelin, N. Bottini, S. M. Stanford, Arthritis Rheumatol.71, 486–495 (2019)). The coding variant resides within the first proline-rich (P1) motif of PTPN22 and results in decreased binding to c-Src kinase (CSK) (X. Dai et al., J. Clin. Invest.123, 2024–2036 (2013); N. Bottini et al., Nat. Genet.36, 337–338 (2004); J. F. Cloutier, A. Veillette, J. Exp. Med.189, 111–121 (1999); T. Vang, J. Nielsen, G. L. Burn, Sci. Signal.11, 1–3 (2018)). Phosphoproteome analysis of T cells expressing the PTPN22(R620W) variant demonstrate enhanced phosphorylation of TCR-activated signaling components including phospholipase CȖ1, IȀBĮ and MAPKs, but also phosphorylation of a _{broader set of substrates than Ptpn22} ^-/- _{T cells (X. Dai et al., J. Clin. Invest. 123, 2024–2036 (2013)).} In addition, subcellular localization of PTPN22(620W) differs from WT PTPN22 to suggest a potential “switch of function” for the at- risk variant (T. Vang et al., Nat. Chem. Biol. (2012), doi:10.1038/nchembio.916; G. L. Burn et al., Sci. Signal.9 (2016), doi:10.1126/scisignal.aaf2195). Human T and B cells expressing the PTPN22(R620W) variant have altered T- and B-cell functions and develop higher frequencies of autoreactive BCR repertoires (M. Rieck et al., J. Immunol.179, 4704–4710 (2007); A. F. Arechiga et al., J. Immunol.182, 3343–3347 (2009); L. Menard et al., J. Clin. Invest.121, 3635–3644 (2011); J. N. Schickel et al., Sci. Immunol.1, 1–9 (2016)). While aged _Ptpn22 ^-/- _{mice on a C57BL/6 genetic background demonstrate expanded numbers of antigen-} experienced T cells and spontaneous formation of germinal centers, a histologic finding often found in autoimmune prone strains of mice, they do not demonstrate any overt autoimmune features unless subjected to a secondary factor such as administration of IFNĮ, crossing to autoimmune-susceptible mice carrying an activating CD45 wedge mutation (E613R) or bred onto a mixed 129 genetic background (K. Hasegawa, F. Martin, G. Huang, Science (80-. ).685, 685–690 (2009); D. A. Holmes et al., J. Exp. Med.212, 1081–1093 (2015); X. Dai et al., J. Clin. Invest.123, 2024–2036 (2013); J. Zikherman et al., J. Immunol.182, 4093–4106 (2009)). [0006] Cancer immunotherapy has evolved from the approval of interferon-alpha (IFNĮ) and interleukin-2 in the 1980s to recent approval of CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While search for novel immunomodulatory agents continue, combination therapies have also increased efficacy. However, the need remains for safer and more effective cancer therapies (e.g., cancer immunotherapies), as well as a greater understanding of immune tolerance thresholds and how they impact prognosis of cancer and responses to cancer immunotherapy. [0007] All references cited herein, including patent applications, patent publications, and UniProtKB/Swiss-Prot Accession numbers are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference. SUMMARY [0008] Provided herein are methods related, e.g., to treatment with a PTPN22 inhibitor and a PD-1 axis binding antagonist (e.g., a PD-L1 binding antagonist or a PD-1 binding antagonist). These methods are based, inter alia, on the demonstration herein that Ptpn22 deficiency and checkpoint blockade translated into a pronounced enhancement of tumor responsiveness in a variety of tumor models with different levels and activation status of infiltrating T cells. Without wishing to be bound to theory, it is thought that inhibition of PTPase activity affords the opportunity to augment cancer immunotherapy through at least two clinically approved classes of therapies and pathways: IFNĮ and TCR signaling. In addition, it was demonstrated that patients homozygous for the PTPN22(R620W) autoimmune susceptibility SNP had longer overall survival when treated with atezolizumab, as compared to all other patients. Thus, genetic variants that can shift an individual’s genetic risk to break tolerance and develop autoimmunity may also protect one’s propensity to develop cancer or mount a more effective immune responses with CPI. [0009] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising: (a) determining that the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and (b) based on the determination, administering to the individual an effective amount of an anti-PD-L1 antibody; wherein the anti-PD- L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR- L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). In some embodiments, the methods further comprise administering to the individual an effective amount of a PTPN22 inhibitor. [0010] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising: (a) determining whether the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and (b1) if the individual is heterozygous or homozygous for the PTPN22 allele encoding a PTPN22(R620W) polypeptide, administering to the individual an effective amount of an anti-PD-L1 antibody; or (b2) if the individual is not heterozygous or homozygous for the PTPN22 allele encoding a PTPN22(R620W) polypeptide, administering to the individual an effective amount of an anti-PD-L1 antibody and a PTPN22 inhibitor; wherein the anti- PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). [0011] In some aspects, provided herein are methods of predicting immune-related adverse events (irAEs) in an individual with cancer who has been or is being treated with an anti-PD-L1 antibody, comprising: determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide, wherein the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual is more likely to develop an irAE during or after treatment with an anti-PD-L1 antibody than an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the irAE is hypothyroidism. In some embodiments, the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR- L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). [0012] In some aspects, provided herein are methods of predicting prognosis of treating an individual having cancer with an anti-PD-L1 antibody, comprising: determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide, wherein the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual has an improved prognosis for treatment with an anti-PD-L1 antibody, as compared to prognosis for treatment of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the individual having the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide is predicted to have longer survival upon treatment with an anti-PD-L1 antibody, as compared to survival of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. [0013] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising administering to the individual an effective amount of a PTPN22 inhibitor and an anti-PD-L1 antibody; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). [0014] In some aspects, provided herein are methods of increasing intratumoral CD8+ T cells in an individual with cancer, comprising administering to the individual an effective amount of a PTPN22 inhibitor and an anti-PD-L1 antibody; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR- L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). [0015] In some embodiments according to any of the embodiments described herein, the administration results in an increase in absolute number of intratumoral CD8+ T cells in the individual, as compared to an absolute number of intratumoral CD8+ T cells in the individual prior to the administration. In some embodiments, the administration results in an increased ratio of intratumoral CD8+ T cells to intratumoral regulatory T cells (Tregs) in the individual, as compared to a ratio of intratumoral CD8+ T cells to intratumoral Tregs in the individual prior to the administration. In some embodiments, the administration results in an increase in central memory (Tcm) CD8+ T cells in secondary lymphoid organs of the individual, as compared to a number of Tcm CD8+ T cells in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in CD8+ effector T (Teff) cells in secondary lymphoid organs of the individual, as compared to a number of CD8+ Teff cells in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in CD4+ Teff cells in secondary lymphoid organs of the individual, as compared to a number of CD4+ Teff cells in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in T cells expressing CXCR3 in secondary lymphoid organs of the individual, as compared to a number of T cells expressing CXCR3 in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in T cells expressing ICOS in secondary lymphoid organs of the individual, as compared to a number of T cells expressing CXCR3 in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in increased expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual, as compared to expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual prior to the administration. In some embodiments, the individual is heterozygous or homozygous for an rs2476601 PTPN22 allele. In some embodiments, the individual is heterozygous or homozygous for an rs6679677 single nucleotide polymorphism (SNP). In some embodiments, the PTPN22 inhibitor inhibits phosphatase activity of PTPN22. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the cancer is colon or colorectal cancer, lymphoma, or liver cancer. In some embodiments, the individual is a human. [0016] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising administering to the individual an effective amount of a PTPN22 inhibitor and a PD-L1 binding antagonist. Also provided herein are methods of increasing intratumoral CD8+ T cells in an individual with cancer, comprising administering to the individual an effective amount of a PTPN22 inhibitor and a PD-L1 binding antagonist. Also provided herein are methods of treating or delaying progression of cancer in an individual, comprising administering to the individual an effective amount of a PTPN22 inhibitor and a PD-1 binding antagonist. Also provided herein are methods of increasing intratumoral CD8+ T cells in an individual with cancer, comprising administering to the individual an effective amount of a PTPN22 inhibitor and a PD-1 binding antagonist. [0017] In some embodiments, the administration results in an increase in absolute number of intratumoral CD8+ T cells in the individual, e.g., as compared to an absolute number of intratumoral CD8+ T cells in the individual prior to the administration. In some embodiments, the administration results in an increased ratio of intratumoral CD8+ T cells to intratumoral regulatory T cells (Tregs) in the individual, e.g., as compared to a ratio of intratumoral CD8+ T cells to intratumoral Tregs in the individual prior to the administration. In some embodiments, the administration results in an increase in central memory (Tcm) CD8+ T cells in secondary lymphoid organs of the individual, e.g., as compared to a number of Tcm CD8+ T cells in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in CD8+ effector T (Teff) cells in secondary lymphoid organs of the individual, e.g., as compared to a number of CD8+ Teff cells in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in CD4+ Teff cells in secondary lymphoid organs of the individual, e.g., as compared to a number of CD4+ Teff cells in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in T cells expressing CXCR3 in secondary lymphoid organs of the individual, e.g., as compared to a number of T cells expressing CXCR3 in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in an increase in T cells expressing ICOS in secondary lymphoid organs of the individual, e.g., as compared to a number of T cells expressing CXCR3 in secondary lymphoid organs of the individual prior to the administration. In some embodiments, the administration results in increased expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual, e.g., as compared to expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual prior to the administration. [0018] Also provided herein are methods of treating or delaying progression of cancer in an individual, comprising: determining that the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and based on the determination, administering to the individual an effective amount of a PD-1 axis binding antagonist. In some embodiments, the methods further comprise administering to the individual an effective amount of a PTPN22 inhibitor. [0019] In some embodiments according to any of the embodiments described herein, the PTPN22 inhibitor inhibits phosphatase activity of PTPN22. In some embodiments, the PTPN22 inhibitor is a competitive inhibitor of PTPN22 phosphatase activity. In some embodiments, the PTPN22 inhibitor is a non-competitive inhibitor of PTPN22 phosphatase activity. In some embodiments, the PTPN22 inhibitor inhibits expression of PTPN22. In some embodiments, the PTPN22 inhibitor comprises an antisense nucleic acid, ribozyme, morpholino, siRNA, shRNA, miRNA, gRNA or sgRNA, or triple helix nucleic acid that inhibits expression of PTPN22. In some embodiments, the PTPN22 inhibitor is an antibody that specifically binds PTPN22. In some embodiments, the PTPN22 inhibitor comprises a means for inhibiting phosphatase activity of PTPN22. In some embodiments, the PTPN22 inhibitor comprises a means for inhibiting expression of PTPN22. [0020] Also provided herein are methods of predicting immune-related adverse events (irAEs) in an individual with cancer who has been or is being treated with a PD-1 axis binding antagonist, comprising determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual is more likely to develop an irAE during or after treatment with a PD-1 axis binding antagonist than an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the irAE is hypothyroidism. [0021] Also provided herein are methods of predicting prognosis of treating an individual having cancer with a PD-1 axis binding antagonist, comprising determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual has an improved prognosis for treatment with a PD-1 axis binding antagonist, as compared to prognosis for treatment of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the individual having the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide is predicted to have longer survival upon treatment with a PD-1 axis binding antagonist, e.g., as compared to survival of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. [0022] In some embodiments according to any of the embodiments described herein, the individual is heterozygous or homozygous for an rs2476601 PTPN22 allele. In some embodiments, the individual is heterozygous or homozygous for an rs6679677 single nucleotide polymorphism (SNP). [0023] In some embodiments according to any of the embodiments described herein, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, cemiplimab, or pembrolizumab. In some embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region (V_H) that comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYA DSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:7) and a light chain variable region (VL) that comprises the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 8). In some embodiments, the anti-PD-L1 antibody comprises a heavy chain that comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYA DSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG (SEQ ID NO:9), and a light chain variable region (V_L) that comprises the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:10). In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab or durvalumab. In some embodiments, the cancer is colon or colorectal cancer, lymphoma, or liver cancer. [0024] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows. BRIEF DESCRIPTION OF THE DRAWINGS [0025] FIGS.1A-1H show that Ptpn22 deficiency enhances anti-PD-L1 mediated anti-tumor responses. WT or Ptpn22-/- mice were inoculated with MC38 tumor cells. Upon tumor establishment (~190 mm3) mice were treated with anti-PD-L1 or isotype control antibody. FIG.1A: Tumor volume of treated mice on a log2 scale. Complete regression (CR) was assigned to mice whose tumor volume were < 32 mm3. Nine days after isotype control or anti-PD-L1 treatment, tissues were collected for immune analysis. Also shown are the number of tumor infiltrating CD8+ T cells and the CD8/Treg ratio for each group (FIG.1B), number of tumor infiltrating tetramer+ CD8+ T cells (FIG.1C), number of CD8+ and CD4+ T cells in draining lymph nodes (dLNs) (FIG.1D), frequency of CD8+ T cell subsets in dLNs (FIG.1E), and expression of CXCR3 and ICOS on dLN CD8+ and CD4+ T cells (FIG.1F). FIGS.1G & 1H show tumor volume and frequency of CRs in CT26 (FIG.1G) and E.G7-OVA (FIG.1H) tumor bearing mice. Results from FIG.1A and FIG.1G are representative of two independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001. [0026] FIGS.1I-1L show that Ptpn22 deficiency increases the frequency and activation of antigen _{experienced cells in dLNs and spleens of anti-PD-L1 treated mice. WT or Ptpn22} ^-/- _{mice were} inoculated with MC38 tumor cells. Upon tumor establishment, mice were treated with anti-PD- L1 or isotype control antibody and tissues were collected on day 9 post-treatment. FIG.1I: Frequency of _CD4 ⁺ _{T cell subsets in dLNs of tumor bearing mice. FIGS. 1J & 1K: Frequency of CD8} ⁺ _{(FIG. 1J)} _{and CD4} ⁺ _{T cell subsets (FIG. 1K) in spleens of tumor bearing mice. FIG. 1L: Frequency of CXCR3} _{and ICOS expressing CD8} ⁺ _{and CD4} ⁺ _{T cells in spleens. * P < 0.05, ** P < 0.01.} [0027] FIGS.1M & 1N show higher levels of activated CD8+ and CD4+ T cells in blood of anti- _{PD-L1 treated Ptpn22} ^-/- _{mice. WT or Ptpn22} ^-/- _{mice were inoculated with MC38 tumor cells. Upon} tumor establishment, mice were treated with anti-PD-L1 or isotype control antibody and tissues were collected on day 9 post-treatment. FIG.1M: frequency of CXCR3, PD1, Ki67, and GZMB expressing CD8+ T cells in blood of tumor bearing mice. FIG.1N: frequency of CXCR3, PD1, Ki67, and GZMB expressing CD4+ T cells in blood of tumor bearing mice. Data are mean ± SD. P values determined by using non-parametric, Mann-Whitney tests. * P < 0.05, ** P < 0.01. [0028] FIGS.1O & 1P show frequency of PD1/LAG3/TIM3 subsets on intratumoral CD8+ T cells (FIG.1O), as well as frequency and MFI of GZMB expression on PD1/LAG3/TIM3 CD8+ T cell subsets (FIG.1P). _{[0029] FIGS. 2A-2E show that tumor rejection in Ptpn22} ^-/- _{mice is dependent on both CD4} ⁺ _and _CD8 ⁺ _{T cells and partly on IFNAR signaling. WT or Ptpn22} ^-/- _{mice were inoculated with Hepa1-} 6.x1 subcutaneously in the left flank. In FIG.2A, tumor volume of untreated mice and waterfall plots depict the frequency of spontaneous regressors (SRs). Seven days after tumors were established (~190 _mm ³ _{), tissues were collected for further analysis. Also shown are the the frequency of CD8} ⁺ _{T cell} _{subsets in dLNs and percent CXCR2} ⁺ _{and ICOS} ⁺ _{expressing CD8} ⁺ _{and CD4} ⁺ _{T cells (FIG. 2B),} _{number of intratumoral CD8} ⁺ _{, CD4} ⁺ _{and Treg cells in WT and Ptpn22} ^-/- _{mice (FIG. 2C), and} _{frequency of GZMB, ICOS, CD69, CD103 and T- bet on intratumoral CD8} ⁺ _{and CD4} ⁺ _{T cells (FIG.} _{2D). FIG. 2E shows tumor volume and waterfall plots of Ptpn22} ^-/- _{Hepa1-6.x1 tumor bearing mice} _{treated with depleting antibodies against CD4} ⁺ _{or CD8} ⁺ _{T cells or a blocking antibody against} IFNAR. Results pooled from 3 independent experiments. Results from FIG.2A are representative of more than 4 independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001. _{[0030] FIGS. 2F-2H show increased frequency and activation of antigen experienced CD8} ⁺ _and _CD4 ⁺ _{T cells in blood of Ptpn22 deficient Hepa1-6 tumor bearing mice. WT or Ptpn22} ^-/- _{mice were} inoculated with Hepa1-6.x1 subcutaneously in the left flank and tissues were collected seven days _{after tumors became established. Shown are (FIG. 2F) frequency of CD4} ⁺ _{T cell subsets in dLNs of} _{tumor bearing mice, (FIG. 2G) frequency of CD8} ⁺ _{and CD4} ⁺ _{T cell subsets and (FIG. 2H)} expression of CXCR3 and ICOS in blood of tumor bearing mice. Results representative of 2 independent experiments. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 _{[0031] FIGS. 2I & 2J show pharmacodynamic depletion of CD4} ⁺ _{and CD8} ⁺ _{T cells and blockade} of IFNAR following antibody treatment. Tumor bearing mice were treated with either depleting anti- _{CD4, anti-CD8 or blocking anti-IFNAR antibodies. FIG. 2I: Frequency of CD4} ⁺ _{and CD8} ⁺ _{T cells in} _{blood and tumors of antibody treated mice after 24 hrs. FIG. 2J: IFNAR MFI on CD4} ⁺ _{and CD8} ⁺ _T _{cells and CD11b} ⁺ _{cells 24 hrs after anti-IFNAR treatment. For each cell population, the results from} isotype are shown on the left, and the results from anti-IFNAR are shown on the right. [0032] FIGS.3A-3D show that PTPN22(C227S) mice phenocopy the spontaneous regressions _{observed in Hepa1-6x1 tumor bearing Ptpn22} ^-/- _{mice. FIG. 3A shows schematic designs for Ptpn22}- ^/- _{, Ptpn22} ^619W/619W _{and Ptpn22} ^227S/227S _k

_{constructs. Point mutations were introduced by} CRISPR using a 141 bp and 130 bp donor oligo sequence for R619W and C227S, respectively. Shown are SEQ ID Nos:19 and 20, respectively. FIG.3B shows PTPN22 protein expression in naïve _{splenic T cells by anti-PTPN22 (3D5) mAb, and FIG. 3C shows purified CD4} ⁺ _{and CD8} ⁺ _{T cells by} _{anti- PTPN22 (P2) pAb from each genotype. In FIG. 3D, WT, Ptpn22} ^-/- _{, Ptpn22} ^619W/619W _and _Ptpn22 ^227S/227S _{mice were inoculated with Hepa1-6.x1 subcutaneously in the left flank. Tumor} volume of untreated mice and waterfall plots depict the frequency of spontaneous regressors (SRs). _{[0033] FIGS. 3E-3G show that}

_{knock-in mice} _{phenocopy Ptpn22} ^-/- _{mice. FIG. 3E: T cell composition of thymus, spleen and LNs of ~8-week-old} _{WT, Ptpn22} ^619W/619W _{and Ptpn22} ^227S/227S _{knock-in mice. FIG. 3F: T cell composition of} _{thymus, spleen and LNs of ~8-week WT and Ptpn22} ^227S/227S _{knock-in mice. FIG. 3G: Splenic} _CD4 ⁺ _{T cell composition of >4-month WT,}

_{knock-in mice.} * P < 0.05, *** P < 0.001. [0034] FIG.3H shows the contributions of scaffolding and PTPase activity of PTPN22 in IFNAR function. NIH3T3 cells were transfected with cDNA vector control or cDNAs encoding WT, PTPN22(R619W) or PTPN22(C227S).24 hrs after transfection, cells were stimulated with rIFNĮ4 (2,000 U/ml) for the indicated time points and whole-cell extracts were analyzed by immunoblotting for phosphorylated STAT1 (top), PTPN22 (middle) and ȕ-actin (bottom). [0035] FIG.3I shows the number of European individuals with genetic data from the clinical trials utilized for analysis of rs2476601 variant. Treatment combinations are abbreviated as follows: Atezo = Atezolizumab monotherapy; A = atezolizumab in combination; B=bevacizumab; C=carboplatin; NabP= nab-paclitaxel; P=paclitaxel; Pem= Pemetrexed; E= Etoposide; G= gemcitabine; SUN=sunitnib; PGC=placebo+GC; Chemo=chemotherapy. NCT numbers are as follows: IMmotion151 (NCT02420821); IMpower110(NCT02409342); IMpower130(NCT02367781); IMpower131(NCT02367794); IMpower132(NCT02657434); IMpower133(NCT02763579); IMpower150(NCT02366143); IMpassion130(NCT02425891); IMvigor010(NCT02450331); IMvigor130(NCT02807636); IMvigor211(NCT02302807). [0036] FIGS.4A-4C show that PTPN22(R620W) is associated with increased risk for hypothyroidism and longer overall survival in atezolizumab (anti-PD-L1) treated cancer patients. Cumulative event plot for hypothyroidism (FIG.4A) and hyperthyroidism (FIG.4C) irAEs in patients treated with atezolizumab as a monotherapy or in combination with chemotherapies across 10 randomized controlled trials. FIG.4B: Kaplan-Maier plot of overall survival of atezolizumab treated patients treated across the same 11 trials. Tick marks designate censoring events. [0037] FIGS.5A-5D show anti-tumor activity of anti-PD-1 antibody treatment using the MC38 tumor model in wild-type or Ptpn22 (PEP) knockout mice. FIG.5A shows tumor volume over time during treatment on a log2 scale. FIG.5B shows Growth Contrast (LN units/day) observed in the indicated treatment groups. FIGS.5C & 5D show tumor volume over time during treatment on a log2 scale for the indicated treatment groups. % of animals achieving a complete response (CR) is also shown. DETAILED DESCRIPTION I. Definitions [0038] Before describing the invention in detail, it is to be understood that this invention is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. [0039] As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like. [0040] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. [0041] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. [0042] The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis – with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist. [0043] The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1, PD-L2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. Specific examples of PD-1 binding antagonists are provided infra. [0044] The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1, B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1. In some embodiments, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1, B7-1. In one embodiment, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L1 binding antagonist is an anti-PD-L1 antibody. Specific examples of PD-L1 binding antagonists are provided infra. [0045] The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1. In some embodiments, the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In one embodiment, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L2 binding antagonist is an immunoadhesin. [0046] The term “PTPN22” as used herein refers to a protein tyrosine phosphatase non-receptor type 22 polypeptide. PTPN22 is known as a member of the non-receptor class 4 sub-family of protein tyrosine phosphatases. In some embodiments, PTPN22 gene, polynucleotide, or polypeptide is a human gene, polynucleotide, or polypeptide. An exemplary and non-limiting PTPN22 gene is represented by NCBI Gene ID No.26191. Synonyms for PTPN22 include LYP, PEP, LYP1, LYP2, PTPN8, PTPN22.5, and PTPN22.6. [0047] “Sustained response” refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2.0X, 2.5X, or 3.0X length of the treatment duration. [0048] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed. [0049] As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals. [0050] As used herein, “delaying progression of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed. [0051] An “effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a particular disorder. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved. [0052] As used herein, “in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual. [0053] A “disorder” is any condition that would benefit from treatment including, but not limited to, chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question. [0054] The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In one embodiment, the cell proliferative disorder is a tumor. [0055] “Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer”, “cancerous”, “cell proliferative disorder”, “proliferative disorder” and “tumor” are not mutually exclusive as referred to herein. [0056] A “subject” or an “individual” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is human. [0057] The term “antibody” herein is used in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity. [0058] An “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with research, diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some embodiments, an antibody is purified (1) to greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of, for example, a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using, for example, Coomassie blue or silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. [0059] “Native antibodies” are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. [0060] The term “constant domain” refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen binding site. The constant domain contains the CH1, CH2 and CH3 domains (collectively, CH) of the heavy chain and the CHL (or CL) domain of the light chain. [0061] The “variable region” or “variable domain” of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domain of the heavy chain may be referred to as “VH.” The variable domain of the light chain may be referred to as “VL.” These domains are generally the most variable parts of an antibody and contain the antigen-binding sites. [0062] The term “variable” refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from the other chain, contribute to the formation of the antigen- binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domains are not involved directly in the binding of an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity. [0063] The “light chains” of antibodies (immunoglobulins) from any mammalian species can be assigned to one of two clearly distinct types, called kappa (“^”) and lambda (“^”), based on the amino acid sequences of their constant domains. [0064] The term IgG “isotype” or “subclass” as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions. [0065] Depending on the amino acid sequences of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called Į, Ȗ, ^, Ȗ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000). An antibody may be part of a larger fusion molecule, formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides. [0066] The terms “full length antibody,” “intact antibody” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below. The terms particularly refer to an antibody with heavy chains that contain an Fc region. [0067] A “naked antibody” for the purposes herein is an antibody that is not conjugated to a cytotoxic moiety or radiolabel. [0068] “Antibody fragments” comprise a portion of an intact antibody, preferably comprising the antigen binding region thereof. In some embodiments, the antibody fragment described herein is an antigen-binding fragment. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. [0069] Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen. [0070] “Fv” is the minimum antibody fragment which contains a complete antigen-binding site. In one embodiment, a two-chain Fv species consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. In a single-chain Fv (scFv) species, one heavy- and one light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a “dimeric” structure analogous to that in a two-chain Fv species. It is in this configuration that the three HVRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six HVRs confer antigen- binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site. [0071] The Fab fragment contains the heavy- and light-chain variable domains and also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. [0072] “Single-chain Fv” or “scFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. Generally, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see, e.g., Pluckthün, in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., (Springer- Verlag, New York, 1994), pp.269-315. [0073] The term “diabodies” refers to antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies may be bivalent or bispecific. Diabodies are described more fully in, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med.9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med.9:129-134 (2003). [0074] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts. Thus, the modifier “monoclonal” indicates the character of the antibody as not being a mixture of discrete antibodies. In certain embodiments, such a monoclonal antibody typically includes an antibody comprising a polypeptide sequence that binds a target, wherein the target-binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, or recombinant DNA clones. It should be understood that a selected target binding sequence can be further altered, for example, to improve affinity for the target, to humanize the target binding sequence, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered target binding sequence is also a monoclonal antibody of this invention. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. In addition to their specificity, monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins. [0075] The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the invention may be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14 (3): 253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed.1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), phage-display technologies (see, e.g., Clackson et al., Nature, 352: 624-628 (1991); Marks et al., J. Mol. Biol.222: 581-597 (1992); Sidhu et al., J. Mol. Biol.338(2): 299-310 (2004); Lee et al., J. Mol. Biol.340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004), and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90: 2551 (1993); Jakobovits et al., Nature 362: 255-258 (1993); Bruggemann et al., Year in Immunol.7:33 (1993); U.S. Pat. Nos.5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio/Technology 10: 779-783 (1992); Lonberg et al., Nature 368: 856-859 (1994); Morrison, Nature 368: 812-813 (1994); Fishwild et al., Nature Biotechnol.14: 845-851 (1996); Neuberger, Nature Biotechnol.14: 826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol.13: 65-93 (1995). [0076] The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see, e.g., U.S. Pat. No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). Chimeric antibodies include PRIMATTZED® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with the antigen of interest. [0077] “Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from a HVR of the recipient are replaced by residues from a HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and/or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol.1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035- 1038 (1995); Hurle and Gross, Curr. Op. Biotech.5:428-433 (1994); and U.S. Pat. Nos.6,982,321 and 7,087,409. [0078] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos.6,075,181 and 6,150,584 regarding XENOMOUSETM technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology. [0079] A “species-dependent antibody” is one which has a stronger binding affinity for an antigen from a first mammalian species than it has for a homologue of that antigen from a second mammalian species. Normally, the species-dependent antibody “binds specifically” to a human antigen (e.g., has a binding affinity (Kd) value of no more than about 1x10-7 M, preferably no more than about 1x10-8 M and preferably no more than about 1x10-9 M) but has a binding affinity for a homologue of the antigen from a second nonhuman mammalian species which is at least about 50 fold, or at least about 500 fold, or at least about 1000 fold, weaker than its binding affinity for the human antigen. The species-dependent antibody can be any of the various types of antibodies as defined above, but preferably is a humanized or human antibody. [0080] The term “hypervariable region,” “HVR,” or “HV,” when used herein refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops. Generally, antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). In native antibodies, H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, N.J., 2003). Indeed, naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol.3:733-736 (1996). [0081] A number of HVR delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia refers instead to the location of the structural loops (Chothia and Lesk J. Mol. Biol.196:901-917 (1987)). The AbM HVRs represent a compromise between the Kabat HVRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software. The “contact” HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below. Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat Numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia Numbering) H2 H50-H65 H50-H58 H53-H55 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101 [0082] HVRs may comprise “extended HVRs” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95- 102 (H3) in the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these definitions. [0083] HVRs may comprise “extended HVRs” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95- 102 (H3) in the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these definitions. [0084] “Framework” or “FR” residues are those variable domain residues other than the HVR residues as herein defined. [0085] The term “variable domain residue numbering as in Kabat” or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. [0086] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest.5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody. [0087] The expression “linear antibodies” refers to the antibodies described in Zapata et al. (1995 Protein Eng, 8(10):1057-1062). Briefly, these antibodies comprise a pair of tandem Fd segments (VH- CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions. Linear antibodies can be bispecific or monospecific. [0088] As use herein, the term “binds”, “specifically binds to” or is “specific for” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that binds to or specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (Kd) of ^ 1^M, ^ 100 nM, ^ 10 nM, ^ 1 nM, or ^ 0.1 nM. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species. In another embodiment, specific binding can include, but does not require exclusive binding. [0089] The term “sample,” as used herein, refers to a composition that is obtained or derived from a subject and/or individual of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics. For example, the phrase “disease sample” and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized. Samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, tumor tissue, cellular extracts, and combinations thereof. In some embodiments, the sample is a sample obtained from the cancer of an individual (e.g., a tumor sample) that comprises tumor cells and, optionally, tumor- infiltrating immune cells. For example, the sample can be a tumor specimen that is embedded in a paraffin block, or that includes freshly cut, serial unstained sections. In some embodiments, the sample is from a biopsy and includes 50 or more viable tumor cells (e.g., from a core-needle biopsy and optionally embedded in a paraffin block; excisional, incisional, punch, or forceps biopsy; or a tumor tissue resection). [0090] By “tissue sample” or “cell sample” is meant a collection of similar cells obtained from a tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a disease tissue/organ. The tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. [0091] A “reference sample”, “reference cell”, “reference tissue”, “control sample”, “control cell”, or “control tissue”, as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject or individual. For example, healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject or individual. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of an individual who is not the subject or individual. In even another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject or individual. [0092] An “effective response” of a patient or a patient's “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for, or suffering from, a disease or disorder, such as cancer. In one embodiment, such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer. [0093] A patient who “does not have an effective response” to treatment refers to a patient who does not have any one of extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer. [0094] A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays as disclosed, for example, in definitions herein. [0095] A cancer or biological sample which “has human effector cells” is one which, in a diagnostic test, has human effector cells present in the sample (e.g., infiltrating human effector cells). [0096] A cancer or biological sample which “has FcR-expressing cells” is one which, in a diagnostic test, has FcR-expressing present in the sample (e.g., infiltrating FcR-expressing cells). In some embodiments, FcR is FcȖR. In some embodiments, FcR is an activating FcȖR. II. Methods [0097] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising: (a) determining that the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and (b) based on the determination, administering to the individual an effective amount of an anti-PD-L1 antibody. In some embodiments, the methods further comprise administering to the individual an effective amount of a PTPN22 inhibitor. In some embodiments, the individual is a human. [0098] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising: (a) determining whether the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and (b1) if the individual is heterozygous or homozygous for the PTPN22 allele encoding a PTPN22(R620W) polypeptide, administering to the individual an effective amount of an anti-PD-L1 antibody; or (b2) if the individual is not heterozygous or homozygous for the PTPN22 allele encoding a PTPN22(R620W) polypeptide, administering to the individual an effective amount of an anti-PD-L1 antibody and a PTPN22 inhibitor. In some embodiments, the individual is a human. [0099] In some aspects, provided herein are methods of predicting immune-related adverse events (irAEs) in an individual with cancer who has been or is being treated with an anti-PD-L1 antibody, comprising: determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide, wherein the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual is more likely to develop an irAE during or after treatment with an anti-PD-L1 antibody than an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the irAE is hypothyroidism. In some embodiments, the individual is a human. [0100] In some aspects, provided herein are methods of predicting prognosis of treating an individual having cancer with an anti-PD-L1 antibody, comprising: determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide, wherein the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual has an improved prognosis for treatment with an anti-PD-L1 antibody, as compared to prognosis for treatment of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the individual having the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide is predicted to have longer survival upon treatment with an anti-PD-L1 antibody, as compared to survival of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the individual is a human. [0101] In some embodiments, provided herein is a method for treating or delaying progression of cancer in an individual, comprising administering to the individual an effective amount of a PTPN22 inhibitor and a PD-L1 binding antagonist. Also provided herein is a method for increasing intratumoral CD8+ T cells in an individual with cancer, comprising administering to the individual an effective amount of a PTPN22 inhibitor and a PD-L1 binding antagonist. In some embodiments, the individual is a human. [0102] In some aspects, provided herein are methods of treating or delaying progression of cancer in an individual, comprising administering to the individual an effective amount of a PTPN22 inhibitor and an anti-PD-L1 antibody. In some embodiments, the individual is a human. [0103] In some aspects, provided herein are methods of increasing intratumoral CD8+ T cells in an individual with cancer, comprising administering to the individual an effective amount of a PTPN22 inhibitor and an anti-PD-L1 antibody. In some embodiments, the individual is a human. [0104] Exemplary anti-PD-L1 antibodies suitable for use in the methods of the present disclosure are described infra. For example, in some embodiments, the anti-PD-L1 antibody comprises: (a) a ^{heavy chain variable region (V} _{H) that comprises an HVR-H1 comprising an amino acid sequence of} GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (VL) that comprises an HVR- L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6). In some embodiments, the anti-PD-L1 antibody is atezolizumab. [0105] In some embodiments, the administration results in an increase in absolute number of intratumoral CD8+ T cells in the individual. In some embodiments, a number of intratumoral CD8+ T cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a number of intratumoral CD8+ T cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a number of intratumoral CD8+ T cells in the individual prior to the administration. In some embodiments, number of intratumoral CD8+ T cells refers to a number of intratumoral CD8+ T cells associated with a particular tumor in the individual or in a sample (e.g., from a tumor biopsy) obtained from the tumor/patient. [0106] In some embodiments, the administration results in an increased ratio of intratumoral CD8+ T cells to intratumoral regulatory T cells (Tregs) in the individual. In some embodiments, a ratio of intratumoral CD8+ T cells to Tregs after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a ratio of intratumoral CD8+ T cells to Tregs after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a ratio of intratumoral CD8+ T cells to Tregs in the individual prior to the administration. In some embodiments, ratio of intratumoral CD8+ T cells to Tregs refers to a ratio of intratumoral CD8+ T cells to Tregs associated with a particular tumor in the individual or in a sample (e.g., from a tumor biopsy) obtained from the tumor/patient. [0107] In some embodiments, the administration results in an increase in central memory (Tcm) CD8+ T cells in secondary lymphoid organs of the individual. In some embodiments, a number of Tcm CD8+ T cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD- L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a number of Tcm CD8+ T cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a number of Tcm CD8+ T cells in the individual prior to the administration. In some embodiments, number of Tcm CD8+ T cells refers to a number of Tcm CD8+ T cells in a sample (e.g., from a biopsy) obtained from one or more secondary lymphoid organs in the patient. [0108] In some embodiments, the administration results in an increase in CD8+ effector T (Teff) cells in secondary lymphoid organs of the individual. In some embodiments, a number of CD8+ Teff cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a number of CD8+ Teff cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a number of CD8+ Teff cells in the individual prior to the administration. In some embodiments, number of CD8+ Teff cells refers to a number of CD8+ Teff cells in a sample (e.g., from a biopsy) obtained from one or more secondary lymphoid organs in the patient. [0109] In some embodiments, the administration results in an increase in CD4+ Teff cells in secondary lymphoid organs of the individual. In some embodiments, a number of CD4+ Teff cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a number of CD4+ Teff cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a number of CD4+ Teff cells in the individual prior to the administration. In some embodiments, number of CD4+ Teff cells refers to a number of CD4+ Teff cells in a sample (e.g., from a biopsy) obtained from one or more secondary lymphoid organs in the patient. [0110] In some embodiments, the administration results in an increase in T cells expressing C-X-C motif chemokine receptor 3 (CXCR3) in secondary lymphoid organs of the individual. In some embodiments, a number of T cells expressing CXCR3 after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a number of T cells expressing CXCR3 after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a number of T cells expressing CXCR3 in the individual prior to the administration. In some embodiments, number of number of T cells expressing CXCR3 refers to a number of T cells expressing CXCR3 cells in a sample (e.g., from a biopsy) obtained from one or more secondary lymphoid organs in the patient. In some embodiments, CXCR3 refers to human CXCR3, e.g., as represented by NCBI Gene ID No.2833. Exemplary and non- limiting CXCR3 polynucleotides and polypeptides are represented by NM_001142797 and NP_001136269, respectively. In some embodiments, expression of CXCR3 polynucleotide (e.g., mRNA) is assayed in T cells. In some embodiments, expression of CXCR3 polypeptide is assayed in T cells. Assays for detecting expression of CXCR3 in T cells are well known in the art and exemplified infra. [0111] In some embodiments, the administration results in an increase in T cells expressing inducible T cell costimulator (ICOS) in secondary lymphoid organs of the individual. In some embodiments, a number of T cells expressing ICOS after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, a number of T cells expressing ICOS after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a number of T cells expressing ICOS in the individual prior to the administration. In some embodiments, number of number of T cells expressing ICOS refers to a number of T cells expressing ICOS cells in a sample (e.g., from a biopsy) obtained from one or more secondary lymphoid organs in the patient. In some embodiments, ICOS refers to human ICOS, e.g., as represented by NCBI Gene ID No.29851. Exemplary and non-limiting ICOS polynucleotides and polypeptides are represented by NM_012092 and NP_036224, respectively. In some embodiments, expression of ICOS polynucleotide (e.g., mRNA) is assayed in T cells. In some embodiments, expression of ICOS polypeptide is assayed in T cells. Assays for detecting expression of ICOS in T cells are well known in the art and exemplified infra. [0112] In some embodiments, the administration results in increased expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual. In some embodiments, expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to a reference or reference value. In some embodiments, expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells after administration of a treatment (e.g., comprising a PTPN22 inhibitor and a PD-L1 binding antagonist of the present disclosure) is compared to expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual prior to the administration. In some embodiments, expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells refers to expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells associated with a particular tumor in the individual or in a sample (e.g., from a tumor biopsy) obtained from the tumor/patient. In some embodiments, Granzyme B refers to human Granzyme B, e.g., as represented by NCBI Gene ID No.3002. Exemplary and non-limiting Granzyme B polynucleotides and polypeptides are represented by NM_001346011 and NP_001332940, respectively. In some embodiments, ICOS refers to human ICOS, e.g., as represented by NCBI Gene ID No.29851. Exemplary and non-limiting ICOS polynucleotides and polypeptides are represented by NM_012092 and NP_036224, respectively. In some embodiments, CD69 refers to human CD69, e.g., as represented by NCBI Gene ID No.969. Exemplary and non-limiting CD69 polynucleotides and polypeptides are represented by NM_001781 and NP_001772, respectively. In some embodiments, T-bet refers to human T-bet, e.g., as represented by NCBI Gene ID No.30009. Exemplary and non- limiting T-bet polynucleotides and polypeptides are represented by NM_013351 and NP_037483, respectively. In some embodiments, expression of the polynucleotide (e.g., mRNA) is assayed in T cells. In some embodiments, expression of the polypeptide is assayed in T cells. Assays for detecting gene expression in T cells are well known in the art and exemplified infra. [0113] As noted herein, a reference value and/or baseline value can be obtained from one individual, from two different individuals or from a group of individuals (e.g., a group of two, three, four, five or more individuals), or can refer to a standard value, e.g., a standard lab value. [0114] In some embodiments, secondary lymphoid organs include one or more of: lymph node(s), Peyer’s patches, adenoids, nasal-associated lymphoid tissue (NALT), tonsils, and spleen, as well as samples obtained therefrom. [0115] Also provided herein is a method for treating or delaying progression of cancer in an individual. In some embodiments, the methods comprise determining that the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and administering to the individual an effective amount of a PD-1 axis binding antagonist (e.g., based on said determination). In some embodiments, the methods further comprise administering to the individual an effective amount of a PTPN22 inhibitor. [0116] Also provided herein is a method for predicting immune-related adverse events (irAEs) in an individual with cancer who has been or is being treated with a PD-1 axis binding antagonist. In some embodiments, the methods comprise determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual is more likely to develop an irAE during or after treatment with a PD-1 axis binding antagonist than an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the irAE is hypothyroidism. [0117] Also provided herein is a method for predicting prognosis of treating an individual having cancer with a PD-1 axis binding antagonist. In some embodiments, the methods comprise determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual has an improved prognosis for treatment with a PD-1 axis binding antagonist, as compared to prognosis for treatment of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, an improved prognosis comprises longer survival upon treatment with a PD-1 axis binding antagonist (e.g., as compared to survival of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide). [0118] Certain aspects of the present disclosure relate to determining, detecting, assaying for a PTPN22 allele, e.g., a wild-type PTPN22 allele or a PTPN22 allele encoding a PTPN22(R620W) polypeptide. In some embodiments, a wild-type PTPN22 allele refers to a PTPN22 allele comprising the sequence of SEQ ID NO:19. In some embodiments, a PTPN22 allele encoding a PTPN22(R620W) polypeptide refers to a PTPN22 allele comprising the sequence of SEQ ID NO:20. [0119] Various methods for determining PTPN22 allele sequence are known in the art. In some embodiments, PTPN22 polynucleotide (e.g., DNA or mRNA) is assayed. For example, reagents that specifically detect wild-type or PTPN22(R620W) polynucleotide (e.g., sequence-specific oligonucleotide probes) can be used, or polynucleotide sequence of a PTPN22 polypeptide from a sample or individual can be determined using standard techniques, including without limitation in situ hybridization, direct sequencing, next-generation sequencing (NGS), nanopore sequencing, sequencing by hybridization, nano-transistor array based sequencing, polony sequencing, scanning tunneling microscopy (STM) based sequencing, or nanowire-molecule sensor based sequencing. [0120] In some embodiments, PTPN22 polypeptide is assayed. For example, reagents that specifically detect wild-type or PTPN22(R620W) polypeptide (e.g., sequence-specific antibodies) can be used, or amino acid sequence of a PTPN22 polypeptide from a sample or individual can be determined using standard techniques. [0121] In some embodiments, presence of an rs2476601 PTPN22 allele is detected. For example, in some embodiments, an individual of the present disclosure is heterozygous or homozygous for an rs2476601 PTPN22 allele. This SNP is known to encode a human PTPN22(R620W) polynucleotide. Exemplary sequences can be found in the NCBI dbSNP and ClinVar (see accession number VCV000008909.3) databases. [0122] In some embodiments, presence of an rs6679677 allele or SNP is detected. For example, in ome embodiments, an individual of the present disclosure is heterozygous or homozygous for an rs6679677 allele or SNP. This SNP is known to be in high linkage disequilibrium with the allele encoding a human PTPN22(R620W) polynucleotide. Exemplary sequences can be found in the NCBI dbSNP database. [0123] Exemplary assays for detecting specific alleles, SNPs, or gene-specific expression (e.g., as described supra) include, without limitation, direct sequencing, denaturing high-performance liquid chromatography (dHPLC), high-resolution melting analysis (HRMA), pyrosequencing, polymerase chain reaction (PCR) to detect specific mutations of interest or to target specific regions of interest, fragment length analysis, cationic conjugated polymer (CCP)-based fluorescence resonance energy transfer (FRET), SmartAMP, peptide nucleic acid (PNA)-mediated PCR clamping, IHC, ARMS, real- time PCR, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). See, e.g., Ellison, G. et al. (2013) J. Clin. Pathol.66:79-89. [0124] In some embodiments according to any of the embodiments described herein, a PTPN22 inhibitor of the present disclosure inhibits phosphatase (e.g., tyrosine phosphatase) activity of PTPN22. In some embodiments, the PTPN22 inhibitor is a competitive inhibitor of PTPN22 phosphatase activity. In some embodiments, the PTPN22 inhibitor is a non-competitive inhibitor of PTPN22 phosphatase activity. In some embodiments, the PTPN22 inhibitor comprises a means for inhibiting phosphatase activity of PTPN22, optionally in a pharmaceutical composition comprising the means for inhibiting phosphatase activity of PTPN22 and a pharmaceutically acceptable carrier. Exemplary assays for phosphatase activity are known in the art. [0125] In some embodiments, the PTPN22 inhibitor inhibits expression of PTPN22. In some embodiments, the PTPN22 inhibitor comprises an antisense nucleic acid, ribozyme, morpholino, siRNA, shRNA, miRNA, gRNA or sgRNA, or triple helix nucleic acid that inhibits expression of PTPN22. In some embodiments, the PTPN22 inhibitor is an antibody that specifically binds PTPN22. In some embodiments, the PTPN22 inhibitor comprises a means for inhibiting expression of PTPN22, optionally in a pharmaceutical composition comprising the means for inhibiting expression of PTPN22 and a pharmaceutically acceptable carrier. III. PD-1 Axis Binding Antagonists [0126] Certain aspects of the present disclosure relate to PD-1 axis binding antagonists and/or PD- L1 binding antagonists. [0127] For example, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PDL1 binding antagonist and a PDL2 binding antagonist. Alternative names for “PD-1” include CD279 and SLEB2. Alternative names for “PDL1” include B7-H1, B7-4, CD274, and B7-H. Alternative names for “PDL2” include B7-DC, Btdc, and CD273. In some embodiments, PD-1, PDL1, and PDL2 are human PD-1, PDL1 and PDL2. [0128] In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partner(s). In a specific aspect the PD-1 ligand binding partners are PDL1 and/or PDL2. In another embodiment, a PDL1 binding antagonist is a molecule that inhibits the binding of PDL1 to its binding partner(s). In a specific aspect, PDL1 binding partner(s) are PD-1 and/or B7-1. In another embodiment, the PDL2 binding antagonist is a molecule that inhibits the binding of PDL2 to its binding partner(s). In a specific aspect, a PDL2 binding partner is PD-1. The antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide. [0129] In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). [0130] In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO2006/121168. In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWY DGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLG (SEQ ID NO:11), and (b) the light chain comprises the amino acid sequence: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRAT GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:12). [0131] In some embodiments, the anti-PD-1 antibody comprises the six HVR sequences from SEQ ID NO:11 and SEQ ID NO:12 (e.g., the three heavy chain HVRs from SEQ ID NO:11 and the three light chain HVRs from SEQ ID NO:12). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO:11 and the light chain variable domain from SEQ ID NO:12. [0132] In some embodiments, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in WO2009/114335. In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGG INPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYW GQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTK PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO:13), and (b) the light chain comprises the amino acid sequence: EIVLTQSPAT LSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:14). [0133] In some embodiments, the anti-PD-1 antibody comprises the six HVR sequences from SEQ ID NO:13 and SEQ ID NO:14 (e.g., the three heavy chain HVRs from SEQ ID NO:13 and the three light chain HVRs from SEQ ID NO:14). In some embodiments, the anti-PD-1 antibody comprises the heavy chain variable domain from SEQ ID NO:13 and the light chain variable domain from SEQ ID NO:14. [0134] In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody. [0135] In some embodiments, the anti-PD-1 antibody is PDR001 (CAS Registry No.1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD1 antibody that blocks the binding of PDL1 and PDL2 to PD-1. [0136] In some embodiments, the anti-PD-1 antibody is cemipilimab, also known as REGN2810, REGN-2810, and LIBTAYO® (Regeneron). Cemipilimab is a human anti-PD1 antibody. [0137] In some embodiments, the anti-PD-1 antibody is BGB-108 (BeiGene). In some embodiments, the anti-PD-1 antibody is BGB-A317 (BeiGene). [0138] In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD1 antibody. [0139] In some embodiments, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD1 antibody. [0140] In some embodiments, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD1 antibody. [0141] In some embodiments, the anti-PD-1 antibody is PF-06801591 (Pfizer). [0142] In some embodiments, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro/AnaptysBio). [0143] In some embodiments, the anti-PD-1 antibody is AM0001 (ARMO Biosciences). [0144] In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD1 antibody that inhibits PD-1 function without blocking binding of PDL1 to PD-1. [0145] In some embodiments, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD1 antibody that competitively inhibits binding of PDL1 to PD-1. [0146] In some embodiments, the PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from a PD-1 antibody described in WO2015/112800 (Applicant: Regeneron), WO2015/112805 (Applicant: Regeneron), WO2015/112900 (Applicant: Novartis), US20150210769 (Assigned to Novartis), WO2016/089873 (Applicant: Celgene), WO2015/035606 (Applicant: Beigene), WO2015/085847 (Applicants: Shanghai Hengrui Pharmaceutical/Jiangsu Hengrui Medicine), WO2014/206107 (Applicants: Shanghai Junshi Biosciences/Junmeng Biosciences), WO2012/145493 (Applicant: Amplimmune), US9205148 (Assigned to MedImmune), WO2015/119930 (Applicants: Pfizer/Merck), WO2015/119923 (Applicants: Pfizer/Merck), WO2016/032927 (Applicants: Pfizer/Merck), WO2014/179664 (Applicant: AnaptysBio), WO2016/106160 (Applicant: Enumeral), and WO2014/194302 (Applicant: Sorrento). [0147] In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 binding antagonist is AMP-224. AMP-224 (CAS Registry No.1422184-00-6; GlaxoSmithKline/MedImmune), also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342. [0148] In some embodiments, the PD-1 binding antagonist is a peptide or small molecule compound. In some embodiments, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO2012/168944, WO2015/036927, WO2015/044900, WO2015/033303, WO2013/144704, WO2013/132317, and WO2011/161699. [0149] In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PD-1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1. In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and VISTA. In some embodiments, the PDL1 binding antagonist is CA-170 (also known as AUPM-170). In some embodiments, the PDL1 binding antagonist is a small molecule that inhibits PDL1 and TIM3. In some embodiments, the small molecule is a compound described in WO2015/033301 and WO2015/033299. [0150] In some embodiments, the PD-1 axis binding antagonist is an anti-PDL1 antibody. A variety of anti-PDL1 antibodies are contemplated and described herein. In any of the embodiments herein, the isolated anti-PDL1 antibody can bind to a human PDL1, for example a human PDL1 as shown in UniProtKB/Swiss-Prot Accession No.Q9NZQ7.1, or a variant thereof. In some embodiments, the anti-PDL1 antibody is capable of inhibiting binding between PDL1 and PD-1 and/or between PDL1 and B7-1. In some embodiments, the anti-PDL1 antibody is a monoclonal antibody. In some embodiments, the anti-PDL1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)₂ fragments. In some embodiments, the anti-PDL1 antibody is a humanized antibody. In some embodiments, the anti-PDL1 antibody is a human antibody. Examples of anti-PDL1 antibodies useful for the methods of this invention, and methods for making thereof are described in PCT patent application WO 2010/077634 A1 and US Patent No.8,217,149, which are incorporated herein by reference. [0151] In some embodiments, the anti-PDL1 antibody comprises a heavy chain variable region and a light chain variable region, wherein: (a) the heavy chain variable region comprises an HVR-H1, HVR-H2, and HVR-H3 sequence of GFTFSDSWIH (SEQ ID NO:1), AWISPYGGSTYYADSVKG (SEQ ID NO:2) and RHWPGGFDY (SEQ ID NO:3), respectively, and (b) the light chain variable region comprises an HVR-L1, HVR-L2, and HVR-L3 sequence of RASQDVSTAVA (SEQ ID NO:4), SASFLYS (SEQ ID NO:5) and QQYLYHPAT (SEQ ID NO:6), respectively. [0152] In some embodiments, the anti-PDL1 antibody is MPDL3280A, also known as atezolizumab and TECENTRIQ® (CAS Registry Number: 1422185-06-5). In some embodiments, the anti-PDL1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain variable region sequence comprises the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYA DSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:7), and (b) the light chain variable region sequence comprises the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 8). [0153] In some embodiments, the anti-PDL1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYA DSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG (SEQ ID NO:9), and (b) the light chain comprises the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:10). [0154] In some embodiments, the anti-PDL1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PDL1 antibody (Merck KGaA, Pfizer). In some embodiments, the anti-PDL1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYAD TVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG (SEQ ID NO:15), and (b) the light chain comprises the amino acid sequence: QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSNRPSGVSN RFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVLGQPKANPTVTLFPPSS EELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQ WKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO:16). [0155] In some embodiments, the anti-PDL1 antibody comprises the six HVR sequences from SEQ ID NO:15 and SEQ ID NO:16 (e.g., the three heavy chain HVRs from SEQ ID NO:15 and the three light chain HVRs from SEQ ID NO:16). In some embodiments, the anti-PDL1 antibody comprises the heavy chain variable domain from SEQ ID NO:15 and the light chain variable domain from SEQ ID NO:16. [0156] In some embodiments, the anti-PDL1 antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc optimized human monoclonal IgG1 kappa anti-PDL1 antibody (MedImmune, AstraZeneca) described in WO2011/066389 and US2013/034559. In some embodiments, the anti-PDL1 antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPG (SEQ ID NO:17), and (b) the light chain comprises the amino acid sequence: EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFS GSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:18). [0157] In some embodiments, the anti-PDL1 antibody comprises the six HVR sequences from SEQ ID NO:17 and SEQ ID NO:18 (e.g., the three heavy chain HVRs from SEQ ID NO:17 and the three light chain HVRs from SEQ ID NO:18). In some embodiments, the anti-PDL1 antibody comprises the heavy chain variable domain from SEQ ID NO:17 and the light chain variable domain from SEQ ID NO:18. [0158] In some embodiments, the anti-PDL1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PDL1 antibody described in WO2007/005874. [0159] In some embodiments, the anti-PDL1 antibody is LY3300054 (Eli Lilly). [0160] In some embodiments, the anti-PDL1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PDL1 antibody. [0161] In some embodiments, the anti-PDL1 antibody is KN035 (Suzhou Alphamab). KN035 is single-domain antibody (dAB) generated from a camel phage display library. [0162] In some embodiments, the anti-PDL1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety. In some embodiments, the anti-PDL1 antibody is CX-072 (CytomX Therapeutics). [0163] In some embodiments, the PDL1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from a PDL1 antibody described in US20160108123 (Assigned to Novartis), WO2016/000619 (Applicant: Beigene), WO2012/145493 (Applicant: Amplimmune), US9205148 (Assigned to MedImmune), WO2013/181634 (Applicant: Sorrento), and WO2016/061142 (Applicant: Novartis). [0164] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. [0165] In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some embodiments, the isolated anti-PDL1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O-linked. N- linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites form an antibody is conveniently accomplished by altering the amino acid sequence such that one of the above-described tripeptide sequences (for N-linked glycosylation sites) is removed. The alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site another amino acid residue (e.g., glycine, alanine or a conservative substitution). [0166] In a still further embodiment, the present disclosure provides for compositions comprising any of the above described anti-PDL1 antibodies in combination with at least one pharmaceutically- acceptable carrier. [0167] In a still further embodiment, the present disclosure provides for a composition comprising an anti-PDL1, an anti-PD-1, or an anti-PDL2 antibody or antigen binding fragment thereof as provided herein and at least one pharmaceutically acceptable carrier. In some embodiments, the anti- PDL1, anti-PD-1, or anti-PDL2 antibody or antigen binding fragment thereof administered to the individual is a composition comprising one or more pharmaceutically acceptable carrier. Any of the pharmaceutically acceptable carriers described herein or known in the art may be used. IV. Antibody Preparation [0168] The antibody described herein is prepared using techniques available in the art for generating antibodies, exemplary methods of which are described in more detail in the following sections. [0169] The antibody is directed against an antigen of interest (e.g., PD-L1, such as a human PD-L1). Preferably, the antigen is a biologically important polypeptide and administration of the antibody to a mammal suffering from a disorder can result in a therapeutic benefit in that mammal. [0170] In certain embodiments, an antibody provided herein has a dissociation constant (Kd) of ^ 1^M, ^ 150 nM, ^ 100 nM, ^ 50 nM, ^ 10 nM, ^ 1 nM, ^ 0.1 nM, ^ 0.01 nM, or ^ 0.001 nM (e.g. 10^-8 M or less, e.g. from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). [0171] In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA) performed with the Fab version of an antibody of interest and its antigen as described by the following assay. Solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (¹²⁵I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)). To establish conditions for the assay, MICROTITER^® multi-well plates (Thermo Scientific) are coated overnight with 5 ^g/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [¹²⁵I]-antigen are mixed with serial dilutions of a Fab of interest. The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20^®) in PBS. When the plates have dried, 150 ^l/well of scintillant (MICROSCINT-20 ^TM; Packard) is added, and the plates are counted on a TOPCOUNT ^TM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays. [0172] According to another embodiment, Kd is measured using surface plasmon resonance assays using a BIACORE^®-2000 or a BIACORE ^®-3000 (BIAcore, Inc., Piscataway, NJ) at 25°C with immobilized antigen CM5 chips at ~10 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl-N’- (3-dimethylaminopropyl)- carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 ^g/ml (~0.2 ^M) before injection at a flow rate of 5 ^l/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20^TM) surfactant (PBST) at 25°C at a flow rate of approximately ^{25 ^l/min. Association rates (k} _on ^{) and dissociation rates (k} _off ^{) are calculated using a simple one-to-} one Langmuir binding model (BIACORE ^® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (Kd) is ^{calculated as the ratio k} _off ^/k _on. ^{See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-} rate exceeds 106 M-1 s-1 by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 25oC of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO ^TM spectrophotometer (ThermoSpectronic) with a stirred cuvette. Chimeric, Humanized and Human Antibodies [0173] In certain embodiments, an antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof. [0174] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non- human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non- human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity. [0175] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci.13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos.5, 821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing SDR (a-CDR) grafting); Padlan, Mol. Immunol.28:489-498 (1991) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling). [0176] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem.272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)). [0177] In certain embodiments, an antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol.5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol.20:450-459 (2008). [0178] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos.6,075,181 and 6,150,584 describing XENOMOUSE^TM technology; U.S. Patent No.5,770,429 describing HUMAB® technology; U.S. Patent No.7,041,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region. [0179] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No.7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005). [0180] Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below. Antibody Fragments [0181] Antibody fragments may be generated by traditional means, such as enzymatic digestion, or by recombinant techniques. In certain circumstances there are advantages of using antibody fragments, rather than whole antibodies. The smaller size of the fragments allows for rapid clearance, and may lead to improved access to solid tumors. For a review of certain antibody fragments, see Hudson et al. (2003) Nat. Med.9:129-134. [0182] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli, thus allowing the facile production of large amounts of these fragments. Antibody fragments can be isolated from the antibody phage libraries discussed above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')₂ fragments (Carter et al., Bio/Technology 10:163-167 (1992)). According to another approach, F(ab') ₂ fragments can be isolated directly from recombinant host cell culture. Fab and F(ab') ₂ fragment with increased in vivo half-life comprising salvage receptor binding epitope residues are described in U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner. In certain embodiments, an antibody is a single chain Fv fragment (scFv). See WO 93/16185; U.S. Pat. Nos.5,571,894; and 5,587,458. Fv and scFv are the only species with intact combining sites that are devoid of constant regions; thus, they may be suitable for reduced nonspecific binding during in vivo use. scFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an scFv. See Antibody Engineering, ed. Borrebaeck, supra. The antibody fragment may also be a “linear antibody”, e.g., as described in U.S. Pat. No.5,641,870, for example. Such linear antibodies may be monospecific or bispecific. Single-Domain Antibodies [0183] In some embodiments, an antibody of the present disclosure is a single-domain antibody. A single-domain antibody is a single polypeptide chain comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No.6,248,516 B1). In one embodiment, a single-domain antibody consists of all or a portion of the heavy chain variable domain of an antibody. Antibody Variants [0184] In some embodiments, amino acid sequence modification(s) of the antibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of the antibody may be prepared by introducing appropriate changes into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics. The amino acid alterations may be introduced in the subject antibody amino acid sequence at the time that sequence is made. Substitution, Insertion, and Deletion Variants [0185] In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Conservative substitutions are shown in Table 3. More substantial changes are provided in Table 1 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. Table 3. Conservative Substitutions.

[0186] Amino acids may be grouped according to common side-chain properties: a. hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; b. neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; c. acidic: Asp, Glu; d. basic: His, Lys, Arg; e. residues that influence chain orientation: Gly, Pro; f. aromatic: Trp, Tyr, Phe. [0187] Non-conservative substitutions will entail exchanging a member of one of these classes for another class. [0188] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g. a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity). [0189] Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol.207:179-196 (2008)), and/or SDRs (a-CDRs), with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001).) In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted. [0190] In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may be outside of HVR “hotspots” or SDRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions. [0191] A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties. [0192] Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody. Glycosylation variants [0193] In certain embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed. [0194] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the present disclosure may be made in order to create antibody variants with certain improved properties. [0195] In one embodiment, antibody variants are provided comprising an Fc region wherein a carbohydrate structure attached to the Fc region has reduced fucose or lacks fucose, which may improve ADCC function. Specifically, antibodies are contemplated herein that have reduced fucose relative to the amount of fucose on the same antibody produced in a wild-type CHO cell. That is, they are characterized by having a lower amount of fucose than they would otherwise have if produced by native CHO cells (e.g., a CHO cell that produce a native glycosylation pattern, such as, a CHO cell containing a native FUT8 gene). In certain embodiments, the antibody is one wherein less than about 50%, 40%, 30%, 20%, 10%, or 5% of the N-linked glycans thereon comprise fucose. For example, the amount of fucose in such an antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. In certain embodiments, the antibody is one wherein none of the N-linked glycans thereon comprise fucose, i.e., wherein the antibody is completely without fucose, or has no fucose or is afucosylated. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng.87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys.249:533-545 (1986); US Pat Appl No US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng.87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107). [0196] Antibody variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); US 2005/0123546 (Umana et al.), and Ferrara et al., Biotechnology and Bioengineering, 93(5): 851-861 (2006). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). [0197] In certain embodiments, the antibody variants comprising an Fc region described herein are capable of binding to an FcȖRIII. In certain embodiments, the antibody variants comprising an Fc region described herein have ADCC activity in the presence of human effector cells or have increased ADCC activity in the presence of human effector cells compared to the otherwise same antibody comprising a human wild-type IgG1Fc region. Fc region variants [0198] In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions. [0199] In certain embodiments, the present disclosure contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcJR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc^RIII only, whereas monocytes express Fc^RI, Fc^RII and Fc^RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol.9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No.5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96^® non-radioactive cytotoxicity assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al., Blood 101:1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al., Int’l. Immunol.18(12):1759-1769 (2006)). [0200] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No.6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No.7,332,581). [0201] Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No.6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem.9(2): 6591-6604 (2001).) [0202] In certain embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues). In an exemplary embodiment, the antibody comprising the following amino acid substitutions in its Fc region: S298A, E333A, and K334A. [0203] In some embodiments, alterations are made in the Fc region that result in altered (i.e., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No.6,194,551, WO 99/51642, and Idusogie et al. J. Immunol.164: 4178-4184 (2000). [0204] Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol.24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.)). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371,826). See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No.5,648,260; U.S. Patent No.5,624,821; and WO 94/29351 concerning other examples of Fc region variants. [0205] The specification is considered to be sufficient to enable one skilled in the art to practice the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES [0206] The present disclosure will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Example 1: Dual enhancement of T-cell and IFN-Į receptor functions through inhibition of PTPN22 for cancer immunotherapy [0207] Cancer immunotherapy has evolved from the approval of interferon-alpha (IFNĮ) and interleukin-2 in the 1980s to recent approval of CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While search for novel immunomodulatory agents continue, combination therapies have also increased efficacy. [0208] The following Examples demonstrate that inhibition of PTPN22, a protein tyrosine phosphatase that desensitizes both IFNAR and T-cell receptor (TCR) signaling, provides a novel strategy for cancer immunotherapy. Additionally, the autoimmune susceptibility PTPN22(R620W) variant was found to be associated with lower risk of developing non-melanoma skin cancer as well as improved overall survival and increased risk for hypothyroidism following atezolizumab treatment. Hence, exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for new targets for cancer immunotherapy. Methods Mice [0209] Ptpn22619W/619W and Ptpn22227S/227S knock-in mice were generated on a C57BL/6 background using CRISPR technology. The sgRNA sequence, designed by Benchling, were AGACTCGGGTGTCCGTTCA for PTPN22(619W) and ACCTGCAGTGAATGCATAT for PTPN22(227S). While the 5’ and 3’ homology arms were 75 and 61 bps for 619W, they are 75 and 42 bps for 227S, respectively. All animal studies were reviewed and approved by Institutional _{Animal Care and Use Committee. Mice whose tumors exceeded acceptable size limits (2,000 mm} ³ ₎ or became ulcerated were euthanized and removed from the study. Cell lines [0210] MC38 murine colon adenocarcinoma cells were obtained from Rienk Offringa. The CT26 mouse colon carcinoma cell line and E.G7-OVA mouse lymphoma cell line (EL4) expressing chicken ovalbumin (OVA) were obtained from ATCC (CRL-2638 and CRL-2113 respectively). The Hepa1-6 Sigma X1 (Hepa1-6.x1) cell line was generated from the Hepa1-6 mouse hepatoma cell line (Sigma, SKU92110305) by passaging in-vivo tumor fragments grown in C57BL/6 mice (Charles River- Hollister). Tumor tissue from the second passage was minced with a pair of scalpels in a 10 cm Petri dish containing 20 ml RPMI 1640, 10% fetal bovine serum (FBS; HyClone, Waltham MA). Tissue _{fragments were transferred into a T75 tissue culture flask and cultured in an incubator at 37} ^o _{C, 5%} CO2 for two days to allow for cellular attachment. The medium was then removed and replaced with fresh growth medium. Contaminating fibroblasts were removed by differential trypsinization. Once a monolayer culture was established and passed a few times in-vitro, the growing cultures were passaged by trypsinization at appropriate intervals and split ratios. Cell lines [0211] All cell lines were tested for Mycoplasma using the MycoAlert Mycoplasma Detection Kit (Lonza) and were cultured in RPMI 1640 medium plus 1% L-glutamine with 10% FBS (HyClone, Waltham MA). Cells in log-phase growth were centrifuged, washed once with Hank’s balanced salt solution (HBSS), counted, and resuspended in 50% HBSS and 50% MatrigelTM (BD Biosciences, San Jose CA) for injection into mice. Antibodies [0212] The following anti-mouse antibodies were used for flow cytometry: CD45 (clone 30-F11), TCRȕ (clone H57-597), Thy1.2 (clone 30-H12), CD4 (clone RM4-5), ICOS (clone C398.4A), CD103 (clone 2E7) and T-bet (clone 4B10) were purchased from BioLegend. CD8Į (clone 53-6.7) was purchased from BD Biosciences. CXCR3 (clone CXCR3-173), Foxp3 (clone FJK-16s), CD69 (clone H1.2F3), CD62L (clone Mel14) and CD44 (clones IM7) were purchased from eBioscience. Anti- human granzyme B (cross-reacts with mouse) (clone MHGB05) was purchased from Life Technologies. LIVE/DEADTM Fixable Dead Cell Stain from Life Technologies was used to gate on live cells. Syngeneic tumor studies [0213] Tumor cells were harvested in log-phase growth and resuspended in HBSS containing MatrigelTM (BD Biosciences, San Jose CA) at a 1:1 ratio. Cells were then implanted subcutaneously _{in the right unilateral thoracic area at 10} ⁵ _{(MC38 and CT26), 3 x 10} ⁶ _{(E.G7-OVA) or 10} ⁷ _(Hepa1- 6x1) cells in 100 ^L of HBSS + MatrigelTM. For tumor growth studies, all animals were monitored and tumors were measured at least twice weekly. For efficacy studies, tumors were monitored until _{they became established and reached a mean tumor volume of ~190 mm} ³ _{(typically 7 to 18 days after} _{cell inoculation depending on the tumor model). Mice with tumors in the range of 130 to 250 mm} ³ were then randomized into treatment groups. Treatment was initiated the next day with either isotype control antibody (anti-gp120 mIgG1) or anti-PD-L1 mIgG1 (clone 6E11) at an initial dose of 10 mg/kg intravenously (IV) followed by 5 mg/kg intraperitoneally (IP) thereafter twice a week for 1 week for pharmacodynamic studies or 3 weeks for efficacy studies. All antibodies were diluted in 20 mM histidine acetate, 240 mM sucrose, and 0.02% polysorbate 20, pH 5.5. Tumor volumes were measured in two dimensions (length and width) using Ultra Cal-IV calipers (Fred V Fowler Co, _{Newton MA) and volume was calculated using the formula: Tumor size (mm} ³ _{) = (length x width} ² _{) x} 0.5. Mouse body weights were measured using an Adventura Pro AV812 scale (Ohaus Corporation, Pine Brook NJ). _{[0214] To deplete circulating CD4} ⁺ _{or CD8} ⁺ _{T cells, mice were intraperitoneally injected three} times a week for three weeks with either 10 mg/kg rat anti-mouse CD8 IgG2b antibody (ATCC- 2.43) or 25 mg/kg rat anti-mouse CD4 IgG2b antibody (GK1.5). Rat IgG2b anti-gp120 was used as the isotype matched control antibody. To block IFNAR, 10 mg/kg mouse anti-IFNAR IgG1 antibody (BP0241, BioXcell, Lebanon NH) was dosed intravenously for the first dose followed by intraperitoneal injection three times a week for 3 weeks. In tumor growth studies, depletion was initiated on the day of tumor inoculation. Tissue processing [0215] To generate single cell suspensions, tumors were cut into 2 to 4 mm pieces, digested for 30 min using the murine Tumor Dissociation Kit from Miltenyi (Miltenyi Biotec, Auburn CA) following the manufacturer’s instructions (Cat.130-096-730) and filtered through a 70-micron nylon filter (Corning, Corning NY). Tumor homogenates were then washed twice with RPMI 1640 media and resuspended in staining buffer (PBS, 0.5% FCS, 5mM EDTA). [0216] Spleens and draining lymph nodes (dLN) were minced on a 70-micron nylon filter (Corning, Corning NY). The flow-through was collected, centrifuged at 1,500 rpm at 2 to 8°C. The supernatant was then aspirated and the cell pellets incubated with 5 ml (spleen) or 3 ml (dLNs) of ACK Lysis Buffer for 5 min at room temperature, followed by two washes with cold RPMI 1640 media. Cell pellets were then resuspended in staining buffer. [0217] Blood samples were incubated with 1 ml/50 ^l blood of ACK Lysis Buffer for 5 min at room temperature, followed by two washes with cold RPMI1640. The cell pellet was then resuspended in staining buffer. Flow Cytometry [0218] For surface staining, cells were first incubated with LIVE/DEADTM Fixable Aqua Dead Cell Stain Kit (Thermo Fischer Scientific, Waltham MA) and with TruStain FcX anti-mouse CD16/32 (BioLegend, San Diego CA) for 5 min in PBS. Cells were then washed with staining buffer, resuspended and surface-stained for 25 min at 4^oC. For intracellular staining, cells were fixed and permeabilized using the eBioscienceTM Intracellular Fixation & Permeabilization Buffer Set (eBioscience, San Diego CA) following the manufacturer’s instructions. [0219] For tetramer staining, tumor lysates were stained with BV421-conjugated peptide-MHCI tetramers for 30 min at 4^oC followed by staining with cell surface markers. Tetramers specific for the following sequences were pooled to a final concentration of 20 ^g/mL: Reps1: AQLANDVVL, Adpgk: ASMTNMELM, Irgq: AALLNSAVL, N4bp2l2: ATINFRRL, Aatf: MAPIDHTTM, Cpne1: SSPYSLHYL, Med12: SSVLFEYM, Dpagt1: SIIVFNLL, Spire1: SAIRSYQV. Sequences for these peptides have previously been reported (Capietto, A.H. et al. (2020) J. Exp. Med. doi:10.1084/jem2019179). Cell transfection [0220] NIH-3T3 cells were grown in 6-well plates. At ~75% confluency, cells were transfected with 2.5 ^g DNA of pCMV6 encoding PTPN22 mutants (Clontech) using Lipofectamine LTX with Plus Reagent (Life Technologies) according to manufacturer’s instruction. Cells were stimulated with 2000 U/ml of recombinant mouse IFN-Į4 (rIFN-Į4, PBL Assay Science) 24 hours after transfection. Western blot analysis [0221] Whole-cell lysates were generated with RIPA lysis buffer (Thermo Fisher Scientific) with protease and phosphatase inhibitors, DTT (1 mM), NaF (10 mM), and PMSF (1 mM). Cell lysates were loaded on a NuPAGE 4-12% Bis-Tris gel (Life Technologies) and transferred using an iBlot Gel transfer device (Invitrogen). Membranes were blocked with 5% milk and 0.2% Tween in PBS. Antibodies specific for pSTAT1 and ACTIN were purchased from Cell Signaling Technology. Anti- PTPN22 antisera (P2) raised against a GST-fusion protein encoding PTPN22(aa 670-740) have been previously described (K. Hasegawa, F. Martin, G. Huang, Science (80-. ).685, 685–690 (2009)). Rabbit monoclonal anti-PTPN22 antibody (Clone 3D5) was generated using an acylated N-term and amidated C-term peptide PERTLESFFLADEDC (SEQ ID NO:21). All antibodies were diluted in blocking buffer and incubated overnight at 4oC. HRP-conjugated goat anti–rabbit secondary antibody (Cell Signaling Technology), ECL reagent (Bio-Rad) and Azure 600 (Azure Biosystems) for bands visualization were used in Western analysis. For IFN-Į stimulation in 3T3 cells, recombinant mouse IFN- Į 4 (rIFN- Į 4) was purchased from PBL Assay Sciences. Analysis of rs2476601 skin cancer association in the UK Biobank [0222] Prior to any analysis, individuals in the British white ancestry cohort were used. Heterozygosity outliers, individuals where inferred gender did not match reported gender, individuals with evidence of sex chromosome aneuploidy, individuals excluded from kinship inference, and individuals with excess relatives were removed. Cases were constructed on the basis of a prefix match to ICD10 code C44 “other and unspecified malignant neoplasm of skin” in phenotype field 40006. All other remaining individuals served as controls. The presence of the rs2476601 risk variant was associated with case control by use of logistic regression (glm in R v3.6.1). The computed odds ratio was adjusted for 10 genotype eigenvectors (as computed by UK Biobank) and gender. Analysis of atezolizumab-treated patients that are homozygous risk at rs2476601 [0223] The association analysis between individuals homozygous for the risk allele at rs2476601 and time to hypothyroidism irAEs and overall survival was performed using a Mixed Effects Cox model (coxme package in R v3.6.1). The model used a binary indicator for homozygous risk status of the individual that allow included a random effects term to account for the differing effect size in each of the atezolizumab trial arms. The mixed effects cox model was also stratified by trial arm to account for differing baseline risk of hypothyroidism irAEs and risk of death in each of the trial arms. Associations were also adjusted for 5 genotype eigenvectors to account for any remaining population stratification in the European individuals analyzed. Results [0224] To analyze whether loss of Ptpn22 may enhance CPI activity, the colon adenocarcinoma _{tumor cell line MC38 was engrafted into ~2 to 3-month-old wildtype (WT) or Ptpn22} ^-/- _{mice. Tumor} _{growth was not affected with loss of Ptpn22 (FIG. 1A). When tumors grew to ~190mm} ³ _{in size, mice} were randomized into isotype control or anti-PD-L1 mAb treatment groups. While 20% of WT mice _{achieved a complete response (CR) with anti-PD-L1 treatment, 45% of Ptpn22} ^-/- _{mice achieved CR} with anti-PD-L1 treatment. Consistent with greater tumor shrinkage, there was a significant increase _{in the absolute number of intratumoral CD8} ⁺ _{T cells, known to play a central role in cancer immunity} as well as an associated increase in the CD8/T regulatory cell (Treg) ratio (FIG.1B) and increased numbers of tumor antigen specific CD8+ T cells as measured by pooled tetramer staining (FIG.1C). _{An increase in CD8} ⁺ _{and also CD4} ⁺ _{T cells was observed in draining LNs (dLNs) of anti-PD-L1} _{treated Ptpn22} ^-/- _{mice (FIG. 1D). Interestingly, there was an expansion of central memory (Tcm)} _CD8 ⁺ _{, effector CD8} ⁺ _{(Teff) and effector CD4} ⁺ _{T cells in dLNs of control treated Ptpn22} ^-/- _mice when compared to WT mice, and was further increased following anti- PD-L1 treatment (FIGS.1E and 1I). This effect was also present in spleens of treated mice where an increase in central and _{effector memory (Tem) T cells was observed in control treated mice and Tem CD8} ⁺ _{T cells were} further increased following PD-L1 blockade (FIGS.1J & 1K). The expansion of antigen _{experienced CD8} ⁺ _{and CD4} ⁺ _{T cells in Ptpn22} ^-/- _{mice was accompanied by an increased expression} of the chemokine receptor CXCR3, highly expressed on effector cells and critical for T cell trafficking and function, as well as increased expression of the activation marker ICOS (FIGS.1F and ^{1L). In addition, CD8+ T cells in blood of anti-PD-L1 treated Ptpn22-/-} _{mice showed higher} expression of CXCR3 as well as PD1, Ki-67, and GZMB, confirming their higher activation and proliferation states (FIG.1M). A similar phenotype for PD1, Ki-67, and GZMB was also observed in blood CD4+ T cells of anti-PD-L1 treated Ptpn22^-/- mice (FIG.1N). _{[0225] Consistent with the expansion of effector/memory T cells in aged (> 4 mo) Ptpn22} ^-/- _mice, these tumor studies in younger mice suggest that Ptpn22 deficiency alone has an effect on antigen experienced cells in dLNs and spleen, but little impact on intratumoral T cell numbers. With PD-L1 blockade, these effects were significantly augmented in secondary lymphoid organs leading to a _{pronounced increase in intratumoral CD8} ⁺ _{T cells. This effect on peripheral T cells is particularly} important given recent findings that intratumoral T cells, especially in responsive patients are replenished by non-exhausted T cells from outside the tumor and that CPIs (e.g., anti-PD-L1) are likely playing an important role in expanding cells in secondary lymphoid organs which then infiltrate the tumor (T. D. Wu et al., Nature.579, 274–278 (2020)). _{[0226] Given the enhanced expansion and activation of peripheral CD8} ⁺ _{T cells following anti- PD-} _{L1 treatment in MC38 tumor bearing Ptpn22} ^-/- _{mice, it was tested whether enhanced anti- tumor} immunity is also observed in other tumor models characterized by either reduced activation or _{infiltration of CD8} ⁺ _{T cells. In CT26 tumor bearing mice, characterized by infiltrating, yet poorly} _{activated CD8} ⁺ _{T cells (H. Xiong et al., Cancer Immunol. Res. 7, 963–976 (2019)), it was observed} _{that anti-PD-L1 treatment significantly increased tumor control leading to 50% CRs in Ptpn22} ^-/- _mice when compared to no CRs in WT mice (FIG.1G). In E.G7-OVA tumors, characterized by low _{infiltration of CD8} ⁺ _{T cells despite expression of a highly immunogenic antigen (H. Xiong et al.,} Cancer Immunol. Res.7, 963–976 (2019)), spontaneous CRs were observed in 30% of control treated _Ptpn22 ^-/- _{mice when compared to no CRs in WT mice. Tumor infiltrating CD8+ T cells from Hepa1-} _{6.x1 tumors of Ptpn22} ^-/- _{mice also showed increased frequency of cells co-expressing PD1, LAG3,} and TIM3 (FIG.1O). It has previously been shown that PD1+LAG3+TIM3+ T cells represent highly activated cells which are still functional (not yet exhausted) and correlate with response to anti-PD-L1 treatment (Xiong, H. et al. (2019) Cancer Immunol. Res.7:963-976). These PD1+LAG3+TIM3+ cells also expressed the highest levels of GZMB (FIG.1P), suggesting that Hepa1-6.x1 tumors from _Ptpn22 ^-/- _{mice have a higher fraction of activated cytotoxic cells.} _{[0227] Treatment with anti- PD-L1 further increased CR rate to 40% in Ptpn22} ^-/- _{mice compared to} _{10% CRs in WT mice (FIG. 1H). These results suggest that Ptpn22} ^-/- _{deficiency can augment anti-} tumor responses in a variety of tumor immune contextures and can sometimes have an anti-tumor effect on its own. _{[0228] To further expand on the possibility that Ptpn22} ^-/- _{deficiency can confer intrinsic tumor} _{control, the Hepa1-6.x1 tumor model which is highly infiltrated by CD8} ⁺ _{T cells was used (H. Xiong} et al., Cancer Immunol. Res.7, 963–976 (2019)). It was hypothesized that in this tumor model, increased activation of infiltrating T cells, rather than increased numbers, could tilt the balance in _{favor of tumor control. Indeed, 50% spontaneous remissions (SRs) were observed in Ptpn22} ^-/- _mice _{compared to no SRs in WT mice (FIG. 2A). This was associated with increases in Tcm CD8} ⁺ _{T cells} _{in dLNs and blood as well as increases in Tcm and Tem CD4} ⁺ _{T cells in blood, but not dLNs (FIGS.} _{2B, 2F, & 2G). These peripheral CD8} ⁺ _{and CD4} ⁺ _{T cells also had increased expression of CXCR3} _{and ICOS similar to the observations in MC38 tumor bearing Ptpn22} ^-/- _{mice (FIGS. 2B & 2H). As} _{this tumor model is already highly infiltrated with CD8} ⁺ _{T cells, no increase in intratumoral CD4} ⁺ _or _CD8 ⁺ _{T cells was observed (FIG. 2C). In fact, a decrease in intratumoral CD4} ⁺ _{, CD8} ⁺ _{and Tregs} _{was observed in Ptpn22} ^-/- _{mice. However, the tumor infiltrating CD8} ⁺ _{T cells from Ptpn22} ^-/- _mice expressed higher levels of the cytolytic marker Granzyme B (GZMB), activation markers ICOS and CD69, adhesion marker CD103 and transcription factor T-bet, markers all associated with activated _{effector cells (FIG. 2D). Expression of GZMB and ICOS were also enhanced in intratumoral CD4} ⁺ _T _{cells from Ptpn22} ^-/- _mice. _{[0229] As PTPN22 plays inhibitory roles in TCR and IFNAR signaling, the contribution of CD4} ⁺ _T _{cells, CD8} ⁺ _{T cells and IFNAR signaling to Hepa1-6x1 tumor rejection was explored further. Ptpn22}- m_{ice were treated with depleting CD4 or CD8 antibodies at the time of tumor inoculation. Total} _{depletion of both intratumoral and blood CD4} ⁺ _{and CD8} ⁺ _{T cells was achieved (FIG. 2I). Anti-tumor} _{immunity was significantly compromised with CD4} ⁺ _{or CD8} ⁺ _{T depletion (FIG. 2E). The} _{requirement for CD4} ⁺ _{T cells for anti-tumor immunity in this model is interesting as recent reports} _{have described the importance of CD4} ⁺ _{T cell help for mounting effective CTL responses and tumor} immunity (E. Alspach et al., Nature.574, 696–701 (2019); T. Ahrends et al., Immunity.47, 848- 861.e5 (2017)). [0230] Since PTPN22 also downregulates IFNAR signaling (D. A. Holmes et al., J. Exp. Med.212, 1081–1093 (2015)), it was investigated whether IFNAR function contributed to the spontaneous _{remissions observed in Ptpn22} ^-/- _{mice. Hepa1-6x1 tumor bearing Ptpn22} ^-/- _{mice were treated with an} _{IFNAR blocking antibody and achieved >90% blockade on CD4} ⁺ _{and CD8} ⁺ _{T cells and >80%} _{blockade on CD11b} ⁺ _{granulocytes (FIG. 2J). Blocking IFNAR signaling had a partial effect and} inhibited about half of the SRs observed in control treated mice (FIG.2E). Together, these results demonstrate that PTPN22 contributes to the spontaneous anti-tumor activity in this model dominantly _{through both CD4} ⁺ _{and CD8} ⁺ _{T cells and, in part, through enhancement of IFNAR activity.} [0231] Since the ability of PTPN22 to modulate anti-tumor immunity can be mediated through its P1 proline rich domain’s interaction with CSK’s SH3 domain and/or through its PTPase activity, mice encoding mouse PTPN22(619W), the orthologue of human PTPN22(620W) with compromised ability to interact with CSK, or PTPN22(227S), a catalytically inactive PTPN22, were generated (FIG.3A). _{Levels of PTPN22 expression in WT, Ptpn22} ^620W/620W _{, and Ptpn22} ^227S/227S _{in total splenic cells} _{as well as in purified CD4} ⁺ _{and CD8} ⁺ _{T cells were comparable (FIGS. 3B-3C). Similar to Ptpn22} ^-/- _{mice and Ptpn22} ^620W/620W _{mice generated on a mixed 129/BL6 genetic background (K. Hasegawa,} F. Martin, G. Huang, Science (80-. ).685, 685–690 (2009); J. Zhang et al., Nat. Genet.43, 902–907 (2011); X. Dai et al., J. Clin. Invest.123, 2024–2036 (2013)), immune cell composition of 6 to 8- _{week old Ptpn22} ^620W/620W _{mice was comparable in number of naïve and effector/memory T cells} in thymus, spleen and lymph nodes when compared to WT mice (FIG.3E). Thymocyte, spleen and _{LN composition of 6 to 8- week old Ptpn22} ^227S/227S _{mice were also similar to WT mice (FIGS. 3E} & 3F). Analysis of older (> 4 months) mice demonstrated increased numbers of splenic _{effector/memory T cells in Ptpn22} ^620W

^W _{and Ptpn22} ^227S/227S _{knock-in mice when compared} _{to WT mice and phenocopies age-matched Ptpn22} ^-/- _{mice (FIG. 3G).} [0232] To analyze the contributions of scaffolding and PTPase functions of PTPN22 to the SRs _{observed in Ptpn22} ^-/- _{mice with the Hepa1-6x1 hepatocarcinoma tumor model, tumor cells were} _{implanted in WT, Ptpn22} ^-/- _{, Ptpn22} ^620W/620W _{or Ptpn22} ^227S/227S _{mice. While SRs were} _{observed in 0 to 17% of WT mice as compared to 67% in Ptpn22} ^-/- _{mice, 67% SRs were also} _{observed in catalytically inactive P}

₂ ^227S/227S _{mice, suggesting that PTPN22 catalytic activity is} required to maximally enhance anti-tumor immunity (FIG.3D). In contrast, only 25% SRs were _{observed in Ptpn22} ^620W/620W _{mice compared to WT mice suggesting PTPN22 scaffolding function} with CSK and potentially other binding partners through the P1 motif only partly contributes to anti- _{tumor immunity in this model. From three independent studies Ptpn22} ^620W/620W _{mice only showed} an average of 36 ± 9 % SR (data not shown). These data suggest that inhibition of PTPN22 phosphatase activity is preferred over inhibition of P1-SH3 interactions and required to achieve full anti-tumor immunity. [0233] To dissect the contributions of catalytic activity and scaffolding function through R620W in the P1 domain in IFNĮ function, vector control, WT, 619W or 227S Ptpn22 cDNAs were transfected into NIH3T3 cells and STAT1 phosphorylation was analyzed following IFNĮ stimulation. While expression of WT PTPN22 resulted in decreased STAT1 phosphorylation, expression of a catalytically inactive PTPN22(227S) resulted in substantially higher STAT1 phosphorylation comparable to vector control (FIG.3H). In contrast, expression of PTPN22(619W) resulted in a level of phosphorylated STAT1 intermediate between WT PTPN22 and PTPN22(227S) or vector control. Hence, the scaffolding function of the P1 motif of PTPN22, likely due to CSK, partially contributes to the inhibitory function of PTPN22 in IFNAR signaling. [0234] The PTPN22(R620W) autoimmune susceptibility SNP is also identified as rs2476601. In a recent GWAS, a non-coding variant rs6679677 near PHTF1 was found to be associated with non- melanoma skin cancer risk (U. E. Liyanage et al., Hum. Mol. Genet.28, 3148–3160 (2019)). As _{rs6679677 is in high linkage disequilibrium with rs2476601 (r} ² _{= 0.97 in the European population of} 1000 Genomes (A. Auton et al., Nature.526, 68–74 (2015)), it was investigated whether rs2476601 was also associated with non-melanoma skin cancer risk in a cohort of 17,426 cases and 319,712 controls defined by cancer ICD10 code C44 in the UK Biobank (see Methods) (C. Bycroft et al., Nature.562, 203–209 (2018)). It was found that carriers of variant corresponding to the PTPN22(R620W) autoimmune risk allele were protected from non-melanoma skin cancer in this _{cohort (OR = 0.89, 95% CI 0.86-0.93, p = 4.6x10} ^-8 _{). Consistent with this protective association, the} allele frequency PTPN22(R620W) variant was highest in populations with lighter skin pigmentation, a risk factor for non-melanoma skin cancer, (0.1007 non-Finnish Europeans and 0.1490 Finnish, gnomAD) as compared to populations with darker skin pigmentation (0.0154 in Africans and 0.0131 South Asians, gnomAD)( K. J. Karczewski et al., bioRxiv, 531210 (2019)). [0235] Development of immune-related adverse events (irAEs), which are thought to be autoimmune in origin, is associated with CPI treatment (C. H. June, J. T. Warshauer, J. A. Bluestone, Nat. Med.23, 540–547 (2017)). It was assessed whether the PTPN22(R620W) variant was associated with risk of hypothyroidism irAEs in patients treated with atezolizumab (anti-PD-L1). The analysis was focused on hypothyroidism as it is common and can, in general, be attributed to the CPI when the CPI is used in combination with chemotherapies. An internal genetic database of 3,657 patients of European ancestry in the safety- evaluable population of 11 randomized controlled trials in which 2,164 patients were treated with atezolizumab as a monotherapy or in combination was scanned (FIG. 3I). In total, 14 and 352 atezolizumab patients were homozygous and heterozygous, respectively, for the autoimmune risk allele, reflecting a slightly lower allele frequency (0.087) than observed in European populations in gnomAD. Hyperthyroidism irAEs are often detected before hypothyroidism, but at lower rates than hypothyroidism in patients treated with cancer immunotherapy, including atezolizumab (Chalan, P. et al. (2018) J. Endocrinol. Invest, doi:10.1007/s30618-017-0778-8). It was found that carrying a single risk allele was sufficient to increase individual risk of hyperthyroidism (FIG.4C; univariable p = 0.0072; HR = 1.89; 95% CI 1.19-3.02). It was found that patients that were homozygous for the risk allele of rs2476601 were more likely to develop atezolizumab-induced hypothyroidism than heterozygous carriers and non-carriers (FIG.4A; p = 0.0043; HR = 4.74; 95% CI 1.62-13.82). Endocrine irAEs have been shown to be associated with longer patient survival during anti-PD-1 treatment (A. M. M. Eggermont et al., JAMA Oncol.6, 519–527 (2019)). Consistent with these observations, atezolizumab-treated patients homozygous at rs2476601 also had longer overall survival when compared to all other patients (FIG.4B; p = 0.014; HR = 0.32; 95% CI 0.13- 0.79). It was confirmed that this observation was treatment-specific as no association was present in the control arms of the trials analyzed (p = 0.88; HR = 1.19; 95% CI 0.26-4.75). No association was observed with OS (p=0.55; 95% CI 0.35-7.04) and hypothyroidism irAEs (p=0.58; 95% CI 0.72-1.77) in the control arms of the trials analyzed, indicating the variant was not prognostic. Additional, no evidence was found for an association between rs2476601 with other common irAEs including rash (p=0.83), pneumonitis (p=0.14), and hepatitis (p=0.69) in atezolizumab treated patients. Hence the Ptpn22(C1858T) variant contributes to higher risk of thyroid irAEs and improved OS with anti-PD-L1 therapy. _{[0236] PTPN22 plays critical roles in setting thresholds for TCR repertoire selection as Ptpn22} ^-/- _{and Ptpn22} ^619W/619W _{mice exhibit altered repertoire selection (K. Hasegawa, F. Martin, G. Huang,} Science (80-. ).685, 685–690 (2009); J. Zhang et al., Nat. Genet.43, 902–907 (2011); X. Dai et al., J. Clin. Invest.123, 2024–2036 (2013); J. N. Schickel et al., Sci. Immunol.1, 1–9 (2016)). In addition, PTPN22 also plays important roles in B-cell autoimmunity as B-lineage specific expression of PTPN22(619W) under a mixed genetic background in mice develop autoreactive B cells and systemic vasculitis (X. Dai et al., J. Clin. Invest.123, 2024–2036 (2013)). Further, healthy individuals bearing one or more copies of PTPN22(R620W) variant have defects in both central and peripheral autoreactive B cell counterselection and upregulation of pathways to promote B cell activation to further promote autoimmunity (L. Menard et al., J. Clin. Invest.121, 3635–3644 (2011)). In atezolizumab-treated patients, individuals homozygous, but not heterozygous, for the rs2476601 variant were more likely to develop hypothyroidism than heterozygous or non-carriers for the risk allele. Consistent with the notion that individuals more likely to break tolerance may also have greater propensity to generate an effective tumor immunity, carriers of rs2476601 were protected from development of non-melanoma skin cancer and patients homozygous for the rs2476601 variant had improved overall survival when compared to heterozygotes or non-carriers when treated with atezolizumab. Hence, genetic variants that can shift an individual’s genetic risk to break tolerance and develop autoimmunity may also protect one’s propensity to develop cancer or mount a more effective immune responses with CPI. In anti-PD-L1 treated cancer patients who are carriers, it was observed that heterozygosity is sufficient to increase risk of developing hyperthyroidism. Yet, homozygosity is required to confer a higher risk for developing hypothyroidism and longer overall survival following atezolizumab treatment. It is thought that this may reflect differences in the sensitivity of these events to immune tolerance thresholds conferred by the rs2476601 variant. [0237] Most human solid tumors can be classified to immune inflamed (~25%), excluded (~50%) or desert (~25%) phenotypes (R. S. Herbst et al., Nature.515, 563–567 (2014)). While CPIs appear to provide greatest benefit to inflamed tumors, efficacy is suboptimal in immune excluded or desert phenotypes. TGFȕ appears to play an important role in establishing the fibroblast and collagen-rich peritumoral stromal microenvironment to exclude immune cells (S. Mariathasan et al., Nature.554, 544–548 (2018); D. V. F. Tauriello et al., Nature.554, 538–543 (2018)). In pre-clinical models, inhibition of TGFȕ alters the stromal microenvironment and enhances immune cell entry and anti- _{tumor immunity. Deletion of Ptpn22 in CD8} ⁺ _{T cells has been demonstrated to overcome the} suppressive effects of TGFȕ and a potential strategy for genetic manipulation of T cells for adoptive anti-tumor cell therapy (R. J. Brownlie et al., Nat. Commun.8 (2017), doi:10.1038/s41467-017- 01427-1). [0238] While it has previously been shown that Ptpn22 deficiency can expand the number and responsiveness of memory and effector T cells in aged mice (K. Hasegawa, F. Martin, G. Huang, Science (80-. ).685, 685–690 (2009)), this effect is present in young tumor bearing mice and further augmented following anti-PD-L1 treatment. Ptpn22 deficiency and PD-L1 blockade combined effectively to expand and activate peripheral T cells as well as increased CXCR3 expressoin and, in _{turn, translate into increased activation and numbers of tumor infiltrating CD8} ⁺ _{T cells in the MC38} adenocarcinoma tumor model. The resulting effect of Ptpn22 deficiency and checkpoint blockade translated into a pronounced enhancement of tumor responsiveness in a variety of tumor models with different levels and activation status of infiltrating T cells. Without wishing to be bound to theory, but given that anti-PD-L1 might work by both expanding non-exhausted peripheral T cells and invigorating the responsiveness of pre-exhausted cells, it is thought that targeting PTPN22 could combine with CPI at different stages of the cancer immunity cycle. Even in the absence of checkpoint blockade, Ptpn22 deficiency led to spontaneous regressions in the Hepa1-6.x1 tumor model characterized by high levels of infiltrating CD8+ T cells. In this tumor immune contexture, absence of Ptpn22 expression also led to increased activation of tumor infiltrating T cells and a higher frequency of activated PD1+LAG3+TIM3+CD8+ T cells. While in various syngeneic tumor models co-expression of these receptors is observed in highly activated and functional cells (H. Xiong et al., Cancer Immunol. Res.7, 963–976 (2019)), prolonged antigenic stimulation in the context of Ptpn 22 deficiency could ultimately favor an exhausted-like phenotype. [0239] These studies also suggest that maximal anti-tumor immunity in pre-clinical studies using the Hepa1-6x1 model system requires inhibition of PTPN22 phosphatase activity as opposed to allostery of the P1 domain of PTPN22 to mimic the PTPN22(R619W) variant. While allosteric inhibitors of the SHP2 PTPase are progressing in the clinic and pre-clinical data suggests efficacy in mutant KRAS tumors (G. S. Wong et al., Nat. Med.24, 968–977 (2018); D. A. Ruess et al., Nat. Med. 24, 954–960 (2018); L. Dardaei et al., Nat. Med.24, 512–517 (2018)), in vivo anti-IFNAR studies with Hepa1-6x1 syngeneic tumors and biochemical studies of IFNAR signaling suggest that full enhancement of IFNAR function is better achieved with PTPase inhibition. It is thought that inhibition of PTPase activity affords the opportunity to augment cancer immunotherapy through at least two clinically approved classes of therapies and pathways- IFNĮ and TCR signaling. As PTPN22 also plays important roles in other signaling pathways, it is possible that additional _{mechanisms can also contribute to anti-tumor immunity. Finally, as Ptpn22} ^-/- _{mice under a C57BL/6} background are healthy and require other factors to manifest autoimmunity, PTPN22 inhibition while augmenting multiple pathways may also provide an improved safety profile as compared to other strategies that combine two or more targeted immunotherapies. Example 2: Anti-tumor activity of anti-PD-1 antibody in the MC38 tumor model in wild-type and PTPN22 knockout mice [0240] This Example describes examining inhibition of PD-1 signaling via anti-PD-1 antibody treatment in wild-type or Ptpn22 (PEP) knockout mice. [0241] For tumor studies, MC38 cells were implanted subcutaneously in the right flank of wild-type or Ptpn22 (PEP) knockout mice. Group size was n=5. Dosing was initiated on Day 0 of the study with anti-PD-1 LALAPG antibody or isotype control. A TIW dosing schedule was used on Days 0, 2, 4, 7, 9, 11, 14, 16, and 18. The study duration was 49 days. [0242] As shown in FIGS.5A, 5C, & 5D, anti-PD-1 response was enhanced in Ptpn22 (PEP) knockout mice vs. wild-type mice. Treatment was well tolerated as indicated by body weight response. Tumors reached group out volume 14 days post inoculation. 80% of animals in the Ptpn22 (PEP) knockout with anti-PD-1 treatment group achieved a complete response, as compared to 40% in the wild-type with anti-PD-1 treatment group and 0% in both isotype treatment groups. [0243] FIG.5B shows the observed growth contrast, amounting to the difference between the average log-fold change in tumor volume for a treatment group and the average log-fold change in tumor volume for the control group over the common time period (indicated by AUC Days). The growth contrast ranks how volumes changed, with negative values indicating anti-tumor effects. These results further highlighted an enhanced anti-PD-1 response in Ptpn22 (PEP) knockout mice vs. wild-type mice.

Claims

CLAIMS What is claimed is: 1. A method of treating or delaying progression of cancer in an individual, comprising: (a) determining that the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and (b) based on the determination, administering to the individual an effective amount of an anti- PD-L1 antibody; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6).

2. The method of claim 1, further comprising administering to the individual an effective amount of a PTPN22 inhibitor.

3. A method of treating or delaying progression of cancer in an individual, comprising: (a) determining whether the individual is heterozygous or homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide; and (b1) if the individual is heterozygous or homozygous for the PTPN22 allele encoding a PTPN22(R620W) polypeptide, administering to the individual an effective amount of an anti-PD-L1 antibody; or (b2) if the individual is not heterozygous or homozygous for the PTPN22 allele encoding a PTPN22(R620W) polypeptide, administering to the individual an effective amount of an anti-PD-L1 antibody and a PTPN22 inhibitor; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6).

4. A method of predicting immune-related adverse events (irAEs) in an individual with cancer who has been or is being treated with an anti-PD-L1 antibody, comprising: determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide, wherein the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual is more likely to develop an irAE during or after treatment with an anti-PD-L1 antibody than an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide.

5. The method of claim 4, wherein the irAE is hypothyroidism.

6. A method of predicting prognosis of treating an individual having cancer with an anti-PD-L1 antibody, comprising: determining whether the individual is homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide, wherein the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide indicates that the individual has an improved prognosis for treatment with an anti-PD-L1 antibody, as compared to prognosis for treatment of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide.

7. The method of claim 6, wherein the individual having the presence of a homozygous PTPN22 allele encoding a PTPN22(R620W) polypeptide is predicted to have longer survival upon treatment with an anti-PD-L1 antibody, as compared to survival of an individual that is not homozygous for a PTPN22 allele encoding a PTPN22(R620W) polypeptide.

8. The method of any one of claims 4-7, wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6).

9. A method of treating or delaying progression of cancer in an individual, comprising administering to the individual an effective amount of a PTPN22 inhibitor and an anti-PD-L1 antibody; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6).

10. A method of increasing intratumoral CD8+ T cells in an individual with cancer, comprising administering to the individual an effective amount of a PTPN22 inhibitor and an anti-PD-L1 antibody; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (V_H) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and (b) a light chain variable region (V_L) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6).

11. The method of any one of claims 2, 3, 9, and 10, wherein the administration results in an increase in absolute number of intratumoral CD8+ T cells in the individual, as compared to an absolute number of intratumoral CD8+ T cells in the individual prior to the administration.

12. The method of any one of claims 2, 3, and 9-11, wherein the administration results in an increased ratio of intratumoral CD8+ T cells to intratumoral regulatory T cells (Tregs) in the individual, as compared to a ratio of intratumoral CD8+ T cells to intratumoral Tregs in the individual prior to the administration.

13. The method of any one of claims 2, 3, and 9-12, wherein the administration results in an increase in central memory (Tcm) CD8+ T cells in secondary lymphoid organs of the individual, as compared to a number of Tcm CD8+ T cells in secondary lymphoid organs of the individual prior to the administration.

14. The method of any one of claims 2, 3, and 9-13, wherein the administration results in an increase in CD8+ effector T (Teff) cells in secondary lymphoid organs of the individual, as compared to a number of CD8+ Teff cells in secondary lymphoid organs of the individual prior to the administration.

15. The method of any one of claims 2, 3, and 9-14, wherein the administration results in an increase in CD4+ Teff cells in secondary lymphoid organs of the individual, as compared to a number of CD4+ Teff cells in secondary lymphoid organs of the individual prior to the administration.

16. The method of any one of claims 2, 3, and 9-15, wherein the administration results in an increase in T cells expressing CXCR3 in secondary lymphoid organs of the individual, as compared to a number of T cells expressing CXCR3 in secondary lymphoid organs of the individual prior to the administration.

17. The method of any one of claims 2, 3, and 9-16, wherein the administration results in an increase in T cells expressing ICOS in secondary lymphoid organs of the individual, as compared to a number of T cells expressing CXCR3 in secondary lymphoid organs of the individual prior to the administration.

18. The method of any one of claims 2, 3, and 9-17, wherein the administration results in increased expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual, as compared to expression of Granzyme B, ICOS, CD69, and/or T-bet in intratumoral CD8+ T cells in the individual prior to the administration.

19. The method of any one of claims 1-18, wherein the individual is heterozygous or homozygous for an rs2476601 PTPN22 allele.

20. The method of any one of claims 1-19, wherein the individual is heterozygous or homozygous for an rs6679677 single nucleotide polymorphism (SNP).

21. The method of any one of claims 2, 3, and 9-20, wherein the PTPN22 inhibitor inhibits phosphatase activity of PTPN22.

22. The method of any one of claims 1-21, wherein the anti-PD-L1 antibody is atezolizumab.

23. The method of any one of claims 1-22, wherein the cancer is colon or colorectal cancer, lymphoma, or liver cancer.

24. The method of any one of claims 1-23, wherein the individual is a human.