CN115572768B - 一种针对弥漫大b细胞淋巴瘤的预后评估及联合治疗 - Google Patents
一种针对弥漫大b细胞淋巴瘤的预后评估及联合治疗 Download PDFInfo
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Abstract
本发明属于生物医药和分子生物学技术领域,具体涉及一种针对弥漫大B细胞淋巴瘤的预后评估及联合治疗。本发明首次确定细胞焦亡与弥漫大B细胞淋巴瘤发生和进展密切相关。基于弥漫大B细胞淋巴瘤中细胞焦亡相关基因的特征,建立了全面的预后模型,准确预测了弥漫大B细胞淋巴瘤患者的预后。进一步的,本发明具体验证了PD‑L1抑制剂BMS1166与细胞焦亡抑制剂DMXAA在弥漫大B细胞淋巴瘤细胞中的协同抗肿瘤作用,表明靶向细胞焦亡联合免疫疗法可能成为弥漫大B细胞淋巴瘤的一种有前途的治疗方法,因此具有良好的实际应用之价值。
Description
技术领域
本发明属于生物医药和分子生物学技术领域,具体涉及一种针对弥漫大B细胞淋巴瘤的预后评估及联合治疗。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
弥漫大B细胞淋巴瘤(DLBCL)是成人中最常见的淋巴恶性肿瘤,具有高度侵袭性和异质性。由于以利妥昔单抗为基础的免疫化疗药物的出现,DLBCL在治疗上取得了重大进展。对于大多数晚期癌症患者,R-CHOP方案(利妥昔单抗、环磷酰胺、阿霉素、长春新碱和强的松)的治愈率可达到60%以上。然而,大约三分之一的患者出现了耐药或复发,难以获得理想的生存时间。因此,需要更多的研究对DLBCL患者进行分层并开发预测模型可以提供更精确的分子亚型,以提供个性化的治疗。
细胞焦亡,也称为炎性坏死,是一种新型的细胞程序性死亡(PCD)方式。其特征是细胞持续膨胀,直到细胞膜破裂,导致细胞内容物释放,并激活炎症反应。细胞焦亡在抗感染和免疫防御中发挥着重要作用。Gasdermin家族成员,包括Gasdermin A(GSDMA)、Gasdermin E(GSDME)和Pejvakin(PJVK或DFNB59)是细胞焦亡最重要的执行者。在各种微生物和内源性刺激下,Gasdermin被细胞焦亡caspase裂解,并将Gasdermin的N-末端结构域***膜中,启动细胞焦亡。越来越多的研究将细胞焦亡与癌症和其他恶性肿瘤联系起来,包括肺癌、卵巢癌和结肠癌。有趣的是,细胞焦亡可能在肿瘤的发生中起到双重作用。一方面,细胞焦亡作为细胞死亡的一种形式抑制了肿瘤的生长。诱导肿瘤细胞发生细胞焦亡可能成为一种有希望的癌症治疗方案。另一方面,在细胞焦亡过程中释放的各种信号通路和炎症介质为肿瘤细胞的生长创造了良好的环境,从而促进了肿瘤的生长。例如,IL-1β和IL-18的释放可能促进癌症的发生和发展。最新研究证实,细胞焦亡和肿瘤免疫微环境之间存在的潜在调节关系。GSDME介导的细胞焦亡通过增加肿瘤浸润性NK细胞和CD8+T细胞杀伤淋巴细胞的能力来抑制肿瘤生长。
近年来,细胞焦亡在肿瘤发生发展过程中的作用机制成为研究热点。细胞焦亡可能在DLBCL的发生发展中具有重要的作用。然而,发明人发现,关于细胞焦亡在DLBCL发生发展中的作用的研究还很少。
发明内容
针对上述现有技术的不足,发明人经长期的技术与实践探索,提供一种针对弥漫大B细胞淋巴瘤的预后评估及联合治疗。本发明首次确定细胞焦亡与DLBCL发生和进展密切相关。基于DLBCL中细胞焦亡相关基因(PRGs)的特征,建立了全面的预后模型,准确预测了DLBCL患者的预后。进一步的,本发明通过研究证明靶向细胞焦亡联合免疫疗法可能成为DLBCL的一种有前途的治疗方法。基于上述研究成果,从而完成本发明。
为实现上述技术目的,本发明采用如下技术方案:
本发明的第一个方面,提供一种用于弥漫大B细胞淋巴瘤预后评估的生物标志物,所述生物标志物选自下列细胞焦亡相关基因中的任意一个或多个:SCAF11、CASP8、CASP9、NLRP1和NLRP6。
本发明通过研究发现,上述细胞焦亡相关基因与弥漫大B细胞淋巴瘤患者预后显著相关,因此基于上述生物标志物构建一个弥漫大B细胞淋巴瘤预后评估模型(命名为PRGsscore),所述弥漫大B细胞淋巴瘤预后评估模型,其计算公式=(-1.971*CASP8 exp.)+(-0.300*CASP9 exp.)+(-0.340*NLRP1 exp.)+(-0.124*NLRP6 exp.)+(6.139*SCAF11 exp.)+(-0.900*TIRAP exp.)。
本发明的第二个方面,提供检测上述生物标志物的物质在制备弥漫大B细胞淋巴瘤预后评估产品中的应用。
其中,所述预后评估至少包括对弥漫大B细胞淋巴瘤患者总生存期(OS)的评估。
本发明的第三个方面,提供一种用于弥漫大B细胞淋巴瘤预后评估的***,所述***包括:
a)分析模块,所述分析模块包含:用于确定受试者的待测样品中选自上述细胞焦亡相关基因表达水平的检测物质,以及;
b)评估模块,所述分析模块包含:根据a)中确定的所述细胞焦亡相关基因表达水平对所述受试者进行预后评估。
本发明的第四个方面,提供细胞焦亡抑制剂联合PD-1抑制剂在制备弥漫大B细胞淋巴瘤药物中的应用。
其中,所述细胞焦亡抑制剂可以为双硫仑,所述PD-1抑制剂可以为BMS1166。
其中,所述双硫仑(Disulfiram,DSF)是新近发现的可以抑制细胞焦亡的药物(CAS号:97-77-8),BMS1166是一种新型PD-1抑制剂(CAS号:1818314-88-3),经试验证明,二者均有抑制弥漫大B细胞淋巴瘤细胞增殖的作用,且该作用呈现剂量和时间依赖性;同时,二者联用产生良好的协同作用。
本发明的第五个方面,提供一种药物组合物,所述药物组合物其活性成分至少包括细胞焦亡抑制剂和PD-1抑制剂。
所述组合物其活性成分至少包括双硫仑和BMS1166组成。二者联用能够显著抑制DLBCL细胞增殖,表明靶向细胞焦亡联合免疫疗法在DLBCL治疗中的良好前景。
本发明的第六个方面,提供一种治疗弥漫大B细胞淋巴瘤的方法,所述方法包括向患者施用上述药物组合物。
与现有技术方案相比,上述一个或多个技术方案具有如下有益效果:
上述技术方案基于6个细胞焦亡相关基因SCAF11、CASP8、CASP9、NLRP1、NLRP6和TIRAP构建了预后模型,将DLBCL患者分为高、低风险组。此外,qRT-PCR进一步证实上述基因在DLBCL细胞系中的表达。生存分析发现,与高风险组相比,低风险组的死亡率更低,生存期更长。单因素及多因素Cox回归分析显示,基于PRGs的风险评分模型是DLBCL患者的独立预后因素(HR>1,P<0.01)。此外,进一通过ROC曲线和列线图验证了该预后模型的出色预测性能。GO和KEGG富集阐明了这些PRG可能参与细胞蛋白修饰过程和JAK-STAT信号通路的调节。值得注意的是,该风险评分与DLBCL免疫特征密切相关,免疫活性升高可能有助于DLBCL的抗肿瘤作用。上述技术方案进一步验证了PD-L1抑制剂BMS1166与细胞焦亡抑制剂DMXAA在DLBCL细胞中的协同抗肿瘤作用。
综上,上述技术方案根据DLBCL中PRGs的特征构建了一个全面的预后模型,能够准确预测DLBCL患者的预后;而靶向细胞焦亡联合免疫疗法可能成为一种有希望的DLBCL替代治疗方法,因此具有良好的实际应用之价值。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明实施例中(A-C)PRGs在DLBCL样本和正常样本中的相对表达。ns,没有统计学意义;*p<0.05;**p<0.01;****p<0.001;*****p<0.0001。(D)PPI网络显示PRGs的相互作用。
图2为本发明实施例中(A-E)六个PRG中的Kaplan-Meier生存分析;(G-H)与风险评分的6个PRGs的相关性分析。
图3为本发明实施例中(A-F)CASP8、CASP9、NLRP1、NLRP6、TIRAP和SCAF11在CD19+B细胞和DLBCL细胞中的相对mRNA表达。
图4为本发明实施例中(A)单变量cox回归分析,(B-C)为9个PRGs与预后相关(P<0.05);LASSO回归分析;基于风险评分、各患者生存状况(低风险组:虚线左侧;高风险组:虚线右侧)以及(D-E)CASP8、CASP9、NLRP1、NLRP6、SCAF11和TIRAP表达热图,在不同队列中分布情况。
图5为本发明实施例中(A-B)Kaplan-Meier方法用于比较不同队列高低风险组间的OS;(C-D)ROC曲线评估不同队列风险评分的预测效率。
图6为本发明实施例中不同队列的单变量分析(分期:肿瘤分化,1~4;ECOG,0~4);(A-B)列线图预测DLBCL患者的1年,3年和5年总生存率(6C);列线图的校准曲线(D);ROC曲线分析(E)。
图7为本发明实施例中高风险组和低风险组之间ImmuneScore(A),StromalScore(B),EstimateScore(C)和肿瘤纯度(D)的比较。比较训练队列(E-F)中低风险和高风险组16种免疫细胞和13种免疫相关途径的富集评分。P值显示ns不显著,*P<0.05,**P<0.01,***P<0.001。
图8为本发明实施例中(A)分析风险评分与免疫检查点的相关性。散点图显示了风险评分与PDCD1(B),LAG3(C),CD40(D)和CTLA4(E)之间的相关性。
图9为本发明实施例中BMS1166和DSF都具有抑制LY1细胞增殖的作用,且该作用呈剂量和时间依赖性(A-B)。BMS1166与DMXAA联合处理浓度比例为(BMS1166)12μM:(DSF)5μM能显著抑制DLBCL细胞增殖(C-D)。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本申请的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
有鉴于此,本发明的一种典型具体实施方式中,提供一种用于弥漫大B细胞淋巴瘤预后评估的生物标志物,所述生物标志物选自下列细胞焦亡相关基因中的任意一个或多个:SCAF11、CASP8、CASP9、NLRP1和NLRP6。
进一步的,所述生物标志物为SCAF11、CASP8、CASP9、NLRP1和NLRP6所组成的组。
本发明通过研究发现,上述细胞焦亡相关基因与弥漫大B细胞淋巴瘤患者预后显著相关,因此基于上述生物标志物构建一个弥漫大B细胞淋巴瘤预后评估模型(命名为PRGsscore),所述弥漫大B细胞淋巴瘤预后评估模型,其计算公式=(-1.971*CASP8 exp.)+(-0.300*CASP9 exp.)+(-0.340*NLRP1 exp.)+(-0.124*NLRP6 exp.)+(6.139*SCAF11 exp.)+(-0.900*TIRAP exp.)。
本发明的又一具体实施方式中,提供检测上述生物标志物的物质在制备弥漫大B细胞淋巴瘤预后评估产品中的应用。
具体的,检测上述生物标志物的物质包括但不限于用于RT-PCR、实时定量PCR、原位杂交、基因芯片和基因测序检测所述生物标志物的表达水平的物质。
所述产品包括但不限于所述生物标志物表达水平的引物、探针、芯片、核酸膜条、制剂或试剂盒等,在此不做具体限定。
本发明的又一具体实施方式中,所述预后评估至少包括对弥漫大B细胞淋巴瘤患者总生存期(OS)的评估。
本发明的又一具体实施方式中,提供一种用于弥漫大B细胞淋巴瘤预后评估的***,所述***包括:
a)分析模块,所述分析模块包含:用于确定受试者的待测样品中选自上述细胞焦亡相关基因表达水平的检测物质,以及;
b)评估模块,所述分析模块包含:根据a)中确定的所述细胞焦亡相关基因表达水平对所述受试者进行预后评估;
本发明的又一具体实施方式中,所述a)分析模块中,所述细胞焦亡相关基因包括选自下列基因中的任意一个或多个:SCAF11、CASP8、CASP9、NLRP1和NLRP6。
进一步的,所述生物标志物为上述SCAF11、CASP8、CASP9、NLRP1和NLRP6组成的组。
所述b)评估模块具体评估流程包括:根据a)中确定的所述细胞焦亡相关基因表达水平,基于预后评估模型进行生存预后评估;
本发明的又一具体实施方式中,所述预后评估模型,其计算公式=(-1.971*CASP8exp.)+(-0.300*CASP9 exp.)+(-0.340*NLRP1 exp.)+(-0.124*NLRP6 exp.)+(6.139*SCAF11 exp.)+(-0.900*TIRAP exp.)。
其中,exp.代表以自然常数e为底的指数函数。
本发明的又一具体实施方式中,所述受试者预后模型指数高于阈值时为高表达,则指示受试者预后较差(总生存期较短,死亡率较高);
受试者预后模型指数低于阈值时为低表达,则指示受试者预后较好(总生存期较长,死亡率较低);
本发明的又一具体实施方式中,所述阈值可以为预后模型的中位风险评分值。
本发明的又一具体实施方式中,提供细胞焦亡抑制剂联合PD-1抑制剂在制备弥漫大B细胞淋巴瘤药物中的应用。
其中,所述细胞焦亡抑制剂可以为双硫仑,所述PD-1抑制剂可以为BMS1166。
其中,所述双硫仑(Disulfiram,DSF)是最近新发现的可以抑制细胞焦亡的药物(CAS号:97-77-8),BMS1166是一种新型PD-1抑制剂(CAS号:1818314-88-3),经试验证明,二者均有抑制弥漫大B细胞淋巴瘤细胞增殖的作用,且该作用呈现剂量和时间依赖性;同时,二者联用产生良好的协同作用。
本发明的又一具体实施方式中,二者联用时,所述BMS1166与双硫仑摩尔比为5-10:1-4;进一步为14:5。
本发明的又一具体实施方式中,提供一种药物组合物,所述药物组合物其活性成分至少包括细胞焦亡抑制剂和PD-1抑制剂。
本发明的又一具体实施方式中,所述药物组合物其活性成分至少包括双硫仑和BMS1166组成。二者联用能够显著抑制DLBCL细胞增殖,表明靶向细胞焦亡联合免疫疗法在DLBCL治疗中的良好前景。
本发明的又一具体实施方式中,所述BMS1166与双硫仑摩尔比为5-10:1-4;进一步为14:5。
所述药物组合物还可以包括至少一种药物非活性成分。
所述药物非活性成分可以是药学上通常使用的载体、赋形剂及稀释剂等。而且,根据通常的方法,可以制作成粉剂、颗粒剂、片剂、胶囊剂、混悬剂、乳剂、糖浆剂、喷雾剂等的口服剂、外用剂、栓剂及无菌注射溶液形式的剂型使用。
所述可以包含的载体、赋形剂及稀释剂等非药物活性成分在领域内是熟知的,本领域普通技术人员能够确定其符合临床标准。
本发明的又一具体实施方式中,所述载体、赋形剂及稀释剂包括但不限于有乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、***胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油等。
本发明的又一具体实施方式中,本发明的药物可通过已知的方式施用至体内。例如通过静脉全身递送。可选地经由静脉内、经皮、鼻内、粘膜或其他递送方法进行施用。这样的施用可以经由单剂量或多剂量来进行。本领域技术人员理解的是,本发明中有待施用的实际剂量可以在很大程度上取决于多种因素而变化,如靶细胞、生物类型或其组织、待治疗受试者的一般状况、给药途径、给药方式等等。
本发明的又一具体实施方式中,所述药物施用对象可以是人和非人哺乳动物,如小鼠、大鼠、豚鼠、兔、狗、猴、猩猩等,优选为人。
本发明的又一具体实施方式中,提供一种治疗弥漫大B细胞淋巴瘤的方法,所述方法包括向患者施用上述药物组合物。
以下结合具体实例对本发明作进一步的说明,以下实例仅是为了解释本发明,并不对其内容进行限定。如果实施例中未注明的实验具体条件,通常按照常规条件,或按照销售公司所推荐的条件;在本发明没有特别限定,均可通过商业途径购买得到。
实施例
材料和方法
研究人群和数据采集
DLBCL患者和正常样本的基因表达信息来自癌症基因组图谱(TCGA)(https://portal.gdc.cancer.gov/projects/TCGA-PAAD/)和基因型组织表达(GTEx)(https://www.gtexportal.org/)。GSE10846和GSE53786的原始CEL数据是从基因表达综合(GEO)数据库中提取的。
识别差异表达的PRGs
从先前的文献中获得了33个与细胞焦亡相关的基因。使用R包“ggplot2”分析和可视化TCGA和GTEx数据库中患者的基因表达谱。为了分析PRGs之间的关系,使用STRING在线工具(http://string-db.org/cgi/)构建PPI网络,并将交互比分>0.4作为截止标准。
PRGs预后模型的构建和验证
为了研究PRGs的预后价值,对训练队列GSE53786进行了单变量Cox分析。筛选预后相关的PRGs(P<0.05),在训练队列中进行了LASSO-Cox回归分析,构建预后模型。风险评分计算公式:风险评分=∑7iXi×Yi(X:系数,Y:基因表达水平)。根据中位风险评分,将患者分为高、低风险组,采用Kaplan-Meier方法比较亚组之间的OS,并使用“timeROC”R包绘制ROC曲线。选取GSE10846作为验证队列,分析方法同上。
风险评分的独立预后分析
收集GEO数据库中DLBCL患者的临床信息,如年龄,分期,化疗方案和东部肿瘤合作组(ECOG)表现评分。应用单变量和多变量Cox回归模型结合风险评分分析回归模型中的变量。构建包含多个独立指标的列线图用于预测患者的预后。为了评估列线图的准确性,应用校准曲线来预测1年,3年和5年的OS。
免疫浸润特征分析
筛选高低风险组之间的差异表达基因(DEGs),并对DEGs进行GO和KEGG富集分析。运用“gsva”R包计算浸润性免疫细胞的评分并评估免疫相关途径的活性。此外,使用“estimate”R包评估免疫微环境的差异。通过相关矩阵分析常见免疫检查点表达与风险评分的相关性。
细胞培养
配置含10%胎牛血清的IMDM完全培养基,将人DLBCL细胞系LY1,LY3,LY8和U2932重悬于IMDM完全培养基中,培养在37℃,含5%CO2的细胞培养箱中。
RNA提取和实时荧光定量PCR检测
使用TRIzol试剂提取风险PRGs的总RNA,接着使用逆转录试剂逆转录成cDNA。扩增反应使用SYBR Green在LightCycler 480II实时PCR***上进行。每个样品的实时PCR以一式三份进行,使用的所有引物都列在补充表S2中。
细胞活性检测
细胞活性检测用于探究BMS1166和DSF对DLBCL细胞的作用。根据药物说明书,使用DMSO完全溶解BMS1166或disulfiram粉末,配置为5mM母液,根据浓度换算公式,使用IMDM培养基将母液稀释为工作液。使用IMDM完全培养基重悬细胞,在96孔板中接种1x104个/ml的细胞。加入BMS1166、DSF或BMS1166+DSF,每个浓度设置3个复孔,并设置对照组,均匀摇晃后将96孔板置于37℃,5%CO2培养箱中。孵育24小时后,每孔加入10μlCCK-8试剂,37℃避光静置4小时。使用酶标仪测定每孔细胞在450nm处的吸光值,根据结果计算细胞活率。
统计分析
所有统计分析是使用R软件(版本:3.6.3)和Graphpad Prism 8实现的。如果没有另行指定,则统计显著性被视为P值小于0.05(*P<0.05;**P<0.01;***P<0.001;****P<0.0001)。
结果
多种细胞焦亡相关基因在DLBCL中异常表达
为了探索PRG在DLBCL中的表达谱特征,评估了PRGs在DLBCL和正常样本中的mRNA表达水平。结果显示,大多数PRGs在DLBCL样本中失调(图1A)。随后,筛选了8个中心基因,包括PJVK,TNF,CASP1,CASP3,CASP5,CASP8,NLRP3和IL18(图1B)。考虑到PRGs在DLBCL中的潜在预后价值,探讨了这些风险PRGs在DLBCL预后中的作用。结果表明,SCAF11的高表达与预后不良有关,而CASP8,CASP9,NLRP1,NLRP6和TIRAP的高表达则是保护因素(图2A-F)。SCAF11与风险评分一致呈正相关,而其他风险基因则呈负相关(图2G-H)。此外,qRT-PCR结果显示,与正常细胞相比,DLBCL细胞系中SCAF11的表达显着增加。然而,CASP8和CASP9,NLRP1,NLRP6和TIRAP的mRNA表达水平在DLBCL细胞系中显着降低(图3A-F)。
构建DLBCL中基于PRGs的预后模型:PRGs score
应用了单变量Cox回归分析,进一步研究了PRGs在训练队列中的预后价值。发现,AIM2、CASP3、CASP5、CASP6、IL18和SCAF11的过度表达与DLBCL患者的预后不良有关(图4A)。选取训练队列中的19个预后基因进行lasso cox回归分析,建立预后模型PRGs score(图4B,C)。风险评分由以下公式得出:风险评分=(-1.971*CASP8 exp.)+(-0.300*CASP9exp.)+(-0.340*NLRP1 exp.)+(-0.124*NLRP6 exp.)+(6.139*SCAF11 exp.)+(-0.900*TIRAP exp.)。根据中位风险评分,训练队列中的患者分为高、低风险组。与高风险组相比,低风险组的死亡率更低和存活时间更长。热图展现了,SCAF11在高风险组中高表达,而CASP8、CASP9、NLRP1、NLRP6和TIRAP在低风险组显著上调(图4D,E)。
PRGs score在DLBCL中的预后价值
进一步验证预后模型的实际应用。Kaplan-Meier曲线表明,在生存率上,高风险组的预后明显低于低风险组(图5A)。在验证队列中获得了类似的结果(图5B)。ROC分析表明,模型在训练队列中显示出令人满意的预测效果(1年AUC=0.787,2年0.848,3年生存0.849)(图5C)和验证队列AUC=1年0.695,2年0.725,3年生存0.779)(图5D)。进一步分析关于病理分期,化疗方案和分期的高风险和低风险组,并使用Sankey图将其可视化(图5E)。一致地,大多数源自GCB的DLBCL患者属于低风险组。这些证据揭示了该模型的突出预测功效和优越性。
构建和验证DLBCL的预测列线图
接下来,应用单变量和多变量Cox回归分析来评估风险评分是否可以作为DLBCL患者的独立预后标志物。在单因素Cox回归分析中,风险评分(P<0.001,HR=3.348,95%CI:2.297-4.480,图6A)是一个潜在的危险因素。多因素Cox回归分析进一步表明,在调整其他混杂因素后,风险评分仍可用作预后因素(P=0.0425,HR=1.928,95% CI:1.022-3.636,图6B)。为了探索一种可靠且可量化的方法,开发一种新型预后列线图,可以根据风险评分和临床特征(如年龄、性别、分期、化疗和ECOG表现评分)预测DLBCL患者的生存情况。列线图可以有效地预测DLBCL患者1年,3年和5年OS的概率(图6C)。校准曲线显示,预测的OS与观察到的OS一致(图6D),ROC曲线(AUC)下的面积分别为1年,3年和5年OS的0.794,0.847和0.849(图6E)。
PRGs socre与DLBCL患者的免疫状态密切相关
进一步探讨了PRGs引起不同风险的潜在生物学作用和机制。为了研究高风险和低风险组之间基因功能和途径的差异,使用“limma”R包(|log2FC|>1,P<0.05)提取差异表达基因(DEGs)。
基于这些DEGs,GO和KEGG富集阐明了这些PRGs可能参与细胞蛋白质修饰过程和JAK-STAT信号通路的调节。鉴于JAK-STAT信号通路与肿瘤免疫环境的强相关性,分析亚组的免疫状态。Estimate算法显示,低风险组的免疫评分显著较高,高风险组和低风险组间肿瘤纯度、估计评分和基质评分无显著差异(图7A-D)。随后,应用ssGSEA比较了16种免疫细胞类型的富集评分和13种免疫相关途径的活性。低风险组的免疫浸润程度明显高于高风险组。此外,低风险组浆细胞样树突状细胞(pDC)、滤泡辅助T细胞(Tfh)、T辅助1细胞(Th1)和肿瘤浸润淋巴细胞(TIL)的活性强于高风险组,而NK细胞和T辅助2细胞(Th2)则相反。此外,低风险组在APC共抑制,T-共刺激,检查点和人白细胞抗原(HLA)中具有更高的免疫途径活性(图7E,F)。鉴于亚组间检查点通路的显著差异以及检查点在免疫治疗中的关键作用,分析风险评分与检查点表达之间的相关性。PDCD1、LAG3和CD40等常见检查点与DLBCL中的风险评分显著相关(图8A)。CD40,LAG3和PDCD1均与风险评分呈负相关(图8B-D),而CTLA4则不然(图8C)。基于这些发现,靶向细胞焦亡与免疫疗法结合可能会提供潜在的治疗益处。
细胞焦亡抑制剂联合PD-1抑制剂在DLBCL中发挥协同抗肿瘤效应
进一步探究PD-1抑制剂联合细胞焦亡抑制剂在DLBCL中的抗肿瘤效应。BMS1166是一种新型PD-1抑制剂(CAS号:1818314-88-3),Disulfiram(DSF)是最近新发现的可以抑制细胞焦亡的药物(CAS号:97-77-8)。细胞增殖检测实验表明BMS1166和DSF都具有抑制LY1细胞增殖的作用,且该作用呈剂量和时间依赖性(图9A-B)。运用CompuSyn软件计算得药物联合指数(CA)≤0.8,表明了BMS1166联合DSF具有较好协同效应。此外,BMS1166与DMXAA联合处理浓度比例为(BMS1166)12μM:(DSF)5μM能显著抑制DLBCL细胞增殖(图9C-D)。这些结果揭示了靶向细胞焦亡联合免疫疗法在DLBCL治疗中的良好前景。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (1)
1.细胞焦亡抑制剂联合PD-1抑制剂在制备治疗弥漫大B细胞淋巴瘤药物中的应用,其特征在于,所述细胞焦亡抑制剂为双硫仑,所述PD-1抑制剂为BMS1166;
所述BMS1166与双硫仑摩尔比为12:5。
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