摘要
目的探讨肿瘤浸润性B细胞对程序性死亡受体(配体)1[programmed death(ligand)1,PD-(L)1]抑制剂治疗效果的影响,阐明B细胞影响免疫治疗的潜在机制。方法通过使用公共数据库中的黑色素瘤患者免疫治疗队列,分析B细胞与无进展生存时间(progression-free survival,PFS)以及免疫治疗响应的关系;使用TC-1和B16-OVA肿瘤细胞对6~8周龄雌性C57BL/6小鼠的皮下及肝脏进行荷瘤,构建肿瘤模型。比较B细胞清除对PD-(L)1抗体治疗效果的影响;对第15天的TC-1肿瘤微环境(tumor microenvironment,TME)进行流式细胞术检测,明确T细胞的数目、功能及表型变化;通过流式细胞术及实时荧光定量聚合酶链式反应(quantitative real-time polymerase chain reaction,qPCR)检测B细胞表面分子以及细胞因子。结果基于ICBatlas公共数据库中的ERP105482数据分析,肿瘤中CD19高表达的黑色素瘤患者PFS较低表达者更长(753 d vs 95 d,HR=0.3,95%CI:0.13~0.65,P=0.003)。B细胞在免疫治疗应答的患者中显著富集(P=0.01)。在小鼠TC-1肝脏荷瘤模型中,PD-(L)1抗体治疗后肿瘤质量明显减小(P<0.01),而B细胞的清除削弱了治疗效果。B细胞通过促进T细胞浸润和功能来增强PD-(L)1抗体治疗,且治疗后B细胞亚群发生变化,表现为PD-1低表达亚群增加(P<0.01)。结论PD-(L)1抗体治疗后,B细胞亚群中PD-1表达的下降可能是B细胞促进PD-(L)1抗体治疗效果的潜在机制。
Objective To investigate the effect of tumor-infiltrating B cells on the therapeutic efficacy of programmed death ligand-1[PD-(L)1]inhibitors and elucidate the potential mechanisms.Methods Based on immunotherapy cohorts for melanoma patients in public databases,the relationship of B cells with progression-free survival(PFS)and response to immune checkpoint inhibitors treatment was analyzed.TC-1 and B16-OVA cells were implanted subcutaneously and in the liver in 6-8-week-old female C57BL/6 mice to establish tumor xenograft models.The effect of B cell clearance on PD-(L)1 therapy was compared.Flow cytometry was performed on the 15th day of TC-1 tumor microenvironment(TME)to confirm the number,function and phenotypic changes of T cells.Flow cytometry and quantitative real-time polymerase chain reaction(qPCR)were used to detect B cell surface molecules and cytokines.Results Based on ERP105482 data from the ICBatlas public database,high CD19 expression in the tumors was associated with longer PFS in melanoma patients(753 vs 95 d,HR=0.3,95%CI:0.13~0.65,P=0.003).B cells were significantly enriched in immunotherapy-responsive patients(P=0.01).In a mouse TC-1 liver-loaded tumor model,PD-(L)1 antibody treatment reduced tumor mass(P<0.01),whereas B-cell clearance attenuated the therapeutic efficacy.B cells enhanced PD-(L)1 antibody treatment by promoting T cell infiltration and function,and the treatment resulted in changes in B cell subsets,as evidenced by an increase in PD-1 low-expressing subsets(P<0.01).Conclusion After PD-(L)1 treatment,a decrease in PD-1 expression on B cell subsets might be one of the potential mechanisms by which B cells enhance the efficacy of PD-(L)1 therapy.
作者
侯俊雷
杨学智
董芬
查皓然
杨菲
朱波
HOU Junlei;YANG Xuezhi;DONG Fen;ZHA Haoran;YANG Fei;ZHU Bo(Institute of Cancer,Second Affiliated Hospital,Army Medical University(Third Military Medical University),Chongqing,400037;Department of Radiology,No.964 Hospital of Chinese PLA,Changchun,Jilin Province,130062;School of Pharmacy&Bioengineering,Chongqing University of Technology,Chongqing,400054;Department of Oncology,PLA Rocket Force Medical Center of PLA,Beijing,100088,China)
出处
《陆军军医大学学报》
CAS
CSCD
北大核心
2024年第8期804-814,共11页
Journal of Army Medical University
基金
国家自然科学基金面上项目(82272808)。
