多靶点屏蔽逆转乙肝相关肝细胞癌杀伤性T细胞功能的研究

T cell exhaustion (TCE) is a state of T cell dysfunction that was commonly seen in many chronic virus infection and cancers. Exhausted T cells substantially blunted the anti-cancer immunity and may greatly contribute to the onset and development of tumor.In the last decade, many studies have demonstrated blocking the major negative regulators of TCE to restore the function of exhausted T cells, some of them showed very inspiring results but raised new problems at meantime. In China, more than 70% of patients with HCC were directly related to chronic HBV infection. Thus, when long-term virus infection and cancer, the two major cause of TCE, met in Chinese HCC patients, TCE showed a much higher priority to be the target of an immunotherapy. In the current study, CD8+T cells of HCC patients from different stage of disease and with different TCE severity will be screened for a global gene expression to identify unknown TCE-related negative coreceptors. Based on this, the expression patterns of TCE-related negative coreceptors on CD8+T cell of Chinese HCC patients will be determined.According to these patterns, we will further establish new "cocktail" antibody therapy to restore the function of exhausted CD8+ T cells with better outcomes and efficiency expected. We believe that our study will seal several major gaps on understanding the immunobiology of CD8+ T cell during chronic infection and cancer, and gain a major step forward to the development of TCE-based anti-HCC immunotherapy.

杀伤性T细胞耗竭（TCE）是慢性病毒感染和肿瘤发病过程中一种常见现象，其发生极大地降低了患者的抗肿瘤能力，促进了肿瘤的发生和进展，因此通过免疫学介入逆转TCE对肿瘤的治疗应具有重要作用。但目前研究发现:利用抗体阻断肿瘤TCE过程中重要的负性调节分子以恢复或部分恢复T细胞抗肿瘤功能,但无法获得满意的治疗效果。HBV肝癌同时存在慢性病毒感染和肿瘤， TCE在肝癌发生发展中的作用应该异常突出，负性调节分子在衰竭性T细胞上的表达模式和作用方式更具有异性。本研究拟通过全基因组芯片比对来自HBV肝癌患者病程中不同时间点（如肝炎、肝硬化、肝癌期）、不同耗竭程度的T细胞相关基因表达的变化，筛选出参与TCE新的负性调节分子，并在此基础上明确我国HBV肝癌患者杀伤性T细胞常见的TCE模式和作用方式，根据这些模式建立同时屏蔽多个负性调节分子的"鸡尾酒"抗体疗法，为HBV肝癌的免疫治疗提供新的理论依据

杀伤性T细胞耗竭（TCE）是慢性病毒感染和肿瘤发病过程中一种常见现象，极大地降低了患者的抗肿瘤能力，促进肿瘤的发生和进展。目前已经发现多种TCE相关分子，如CTLA-4, PD1, TIM3, LAG3等，在感染性疾病（HIV、HCV等）及肿瘤中这些分子在T细胞表面的表达与TCE密切相关，表达这些分子的CD8+T细胞丢失效应功能，不能分泌效应细胞因子及杀伤肿瘤细胞，这些T细胞在外周血及瘤内高比例的存在与患者不良的预后密切相关。本项目通过对肝癌患者外周血CD8+T细胞表面的PD-1、Tim-3、LAG-3以及CD160等分子进行了表达水平的分析检测，分析了免疫检查点分子在CD8+T细胞的表达情况，并且通过对PD-1、Tim-3进行阻断，判断其对T 细胞杀伤功能的影响，进一步，对CD160、PD-1在T细胞上双阳性高表达的患者进行临床分析，经过分析，课题组得出了PD-1、Tim-3双阳性高表达的细胞亚群为记忆T细胞（CD44hiCD62hi），发现CD160、PD-1在T细胞上双阳性高表达的患者预后较差，CD160在CD8T细胞上显著高表达，有可能是肝癌的一种新靶标，可以作为今后HBV相关HCC免疫检查点治疗的新方向。