IL-6/STAT3/SOCS3信号途径在胃癌CD8+T细胞免疫功能缺陷中的作用

Great attention has been paid to the fact that chronic inflamation plays a critical role in tumorigenesis, a process during which immunoedting has been proven to contribute to cancer development and deregulation of the immune system. The molecular mechanism of how tumor cells interact with the immune system is not yet clear,especially how tumor cells inhibit the cytoxicity of CD8+ T lymphocytes, resulting in the dissemination of tumor cells. In our previous studies on the gene expression of CD8+ T lymphocytes isolated from peripheral blood of patients with gastric cancer by microarray, SOCS3, a key negative regulated factor in the cytokines/STAT3/SOCS3 signaling pathway was found to be over-expressed in peripheral blooding CD8+T lymphocytes, but in the gastric carcinoma microenvironment,its expression was down-regulated. It has been reported that the activation of STAT3/SOCS3 by IL-6 transsignaling could promote the progression of pancreatic cancer. CD8+ T lymphocytes found in solid tumors are involved in tumor promotion, progression, or metastasis. Here we hypothesize that peripheral blood CD8+T lymphocytes and microenviromental CD8+T lymphocytes play different roles in the cytokine/STAT3/SOCS3 signaling pathway. Microenvironmental CD8+T lymphocytes and gastric cancer cells also found to play different roles in the cytokine/STAT3/SOCS3 signaling pathway. The gene expression profiles of the cytokine/STAT3/SOCS3 signaling pathway will be investigated in both the gastric carcinoma tissue and peripheral blood of patients with gastric carcinoma. To confirm this hypothesis, gastric carcinoma cell lines will co-cultured with CD8+T lymphocytes to study the roles of the cytokine/STAT3/SOCS3 signaling pathway in the mechanisms of functional deficiency of CD8+ T lymphocytes edited by tumor cells and tumor microenvironment. The techniques of high-throughput cDNA expression profile chips,flow cytometric sorting analysis,RNA interference and cell culture will be used to verify its molecular mechanism. This study will provide the fundation to support the use of CD8+ T lymphocytes-based cellular immunotherapy for cancer.

慢性炎症导致肿瘤发生的机制越来越多被重视。免疫系统在肿瘤的发生过程中具有免疫编辑的作用，而肿瘤细胞在与机体免疫系统相互作用中对CD8+T细胞杀伤功能缺陷影响的分子机制尚未阐明。我们前期研究发现胃癌患者免疫分子网络发生显著变化，其中外周血CD8+T细胞在细胞因子/STAT3/SOCS3信号途径中SOCS3高表达，而在肿瘤微环境中SOCS3低表达。我们推测在局部肿瘤进行性生长过程中，肿瘤微环境和外周血中的CD8+T细胞的生物学功能改变不同，细胞因子/STAT3/SOCS3信号途径发挥主要作用。为证实这一假说，我们将采用高通量的表达谱芯片、流式细胞分选、MiRNA干扰等技术，从外周血-肿瘤微环境-细胞三个层次，观察肿瘤细胞对CD8+T细胞的功能编辑以及其信号传导通路的影响。本课题将从新的角度阐明肿瘤细胞对免疫细胞的生物学编辑作用及其分子机制，为以CD8+T细胞为主的肿瘤免疫治疗提供新的理论依据。

本项目完成的研究工作提示①胃癌患者血清中高水平的IL-7、IL-8、IL-17A、TNF-α、ITAC、Fractalkine、可能与胃癌的发生及发展有关，各细胞因子之间的相互作用、相互影响也与肿瘤的发生有着一定的关系。IL-8、IL-17A、TNF-α高表达可能是预后不良的指标，可为临床诊断、病情监测、预后判断提供免疫学依据，抑制其表达可作为治疗胃癌的方向之一。②胃癌患者外周血T淋巴细胞亚群CD3、CD4表达降低，CD8升高，且CD4+、CD8+T细胞表面PD-1表达显著增高，并与胃癌患者临床病理特征密切相关，PD-1可能成为预测胃癌进展和预后的新分子标志物，阻断PD-1/PD-L1信号通路有望成为改善胃癌免疫治疗效果的新策略 。