PD-L1在外周T细胞淋巴瘤微环境中的表达及免疫调节功能

Peripheral T-cell lymphoma（PTCL）is one of the most aggressive subtypes of non-Hodgkins’ lymphoma(NHL), which is insensitive to conventional chemotherapy regimens. Currently, effective targeted agents for PTCL therapy are lacking. Therefore, the identification of novel therapeutic targets is a major and important challenge in PTCL treatment. Recent study shows that immue evasion mediated by tumor microenvironment is closely associated with tumor development and progression, but its precise role in PTCL remains unclear. Our preliminary data indicate that over expression of PD-L1 in the tumor stromal cells in PTCL microenvironment is associated with poor clinical outcome, and suggests that immune evasion mediated by PD-L1 may play an important role in the pathogenesis and progression of PTCL. The current research project will (1) identify the key cytokines responsible for inducing high PD-L1 expression in the tumor stomal cells in PTCL microenvironment; and (2) explore and validate novel strategies to supress expression of PD-L1 in PTCL stomal cells by directly or indirectly blocking the signaling pathways that regulate PD-L1 expression, with a major goal to lay a foundation for the development of new effective therapy for PTCL.

外周T细胞淋巴瘤（peripheral T cell lymphoma,PTCL）是最具侵袭性的非霍奇金淋巴瘤类型之一，常规化疗效果差。目前缺乏有效的靶向治疗药物，亟需新的治疗策略。近年研究发现肿瘤微环境中免疫逃逸与肿瘤的发生发展密切相关，但其在PTCL发生发展中的作用尚不清楚。我们前期研究发现PTCL的微环境细胞高表达程序性死亡受体配体-1（programmed death 1 ligand，PD-L1），并且与预后不良密切相关，提示微环境细胞PD-L1介导的免疫逃逸可能在PTCL的发生发展中起关键作用。本项目拟研究：(1)寻找可诱导PTCL微环境细胞PD-L1升高的关键细胞因子；(2)从直接阻断及间接阻断PD-L1信号通路两方面着手，探索和验证有效干预微环境细胞PD-L1过度表达的策略，为发现PTCL新的治疗方案提供理论基础和实验依据。

研究目的：外周T细胞淋巴瘤（Peripheral T-cell Lymphoma，PTCL）是高度侵袭性的T细胞性非霍奇金淋巴瘤，晚期和复发/难治性患者目前缺乏有效治疗手段，预后较差。PTCL肿瘤组织中存在PD-L1的表达，然而，肿瘤细胞的PD-L1表达水平对PTCL患者预后和免疫治疗疗效的预测价值仍存在争议。PTCL肿瘤微环境中的非肿瘤细胞也有PD-L1表达，可能在肿瘤免疫逃逸中发挥重要作用，但其临床、预后及疗效预测价值仍有待研究。本课题旨在：（1）检验PTCL肿瘤微环境细胞中PD-L1的表达水平并探索其调控机制；（2）探索外周血和组织中各类肿瘤微环境细胞PD-L1的表达水平与PTCL患者临床特征和预后的关系。..研究方法：（1）构建PTCL肿瘤细胞与人骨髓基质细胞共培养模型，使用real-time PCR、western blotting、流式细胞术和免疫荧光方法检测共培养前后的基质细胞PD-L1表达水平；（2）分别使用高通量蛋白组学芯片及血浆ctDNA测序筛选调控PTCL肿瘤微环境中细胞PD-L1表达的关键因子和信号通路，并通过western blotting进一步验证；（3）分别采用流式细胞术及免疫多染方法，检测PTCL患者的外周血及石蜡组织样本中多种免疫细胞的PD-L1表达水平，并分析其与临床特征及预后的关系。..研究结论：（1）PTCL细胞通过激活PI3K-Akt信号通路上调肿瘤微环境中基质细胞PD-L1的表达；（2）PTCL患者外周血和肿瘤组织中存在多种免疫细胞的PD-L1高表达，与不良临床特征和预后显著相关。