TNFR2+调节性T细胞在肺癌免疫耐受中的作用及机制研究

Regulatory T cells (Treg) maintain self-tolerance and immune stability at the same time suppress the immune system on tumor immune response. New therapeutic strategies should stimulate effector T cells while clear Treg cells. In recent years, the studies on CD4+CD25+TNFR2+T cells have aroused great interest of researchers.TNFR2 highly expresses on the suface of treg cells of normal mice, mice mode with tumor and normal human beings. The TNFR2+Treg accounted for 75%-100% of CD4+CD25+Tregs, and it performs four times immunosuppressive function than the subtype of CD4+CD25+T cells. After the treatment of cyclophosphamide, removing the TNFR2+Treg cells could eliminate the tumor cells. The result of pre-experiment in our study team showed that TNFR2 is highly expressed on the Tregs of patients with lung cancer and significantly higher expression than that on non-Tregs. After incubation with tumor cell lines, the expression of Foxp3 and TNFR2 of CD4+CD25-T cells elevated at the same time. This study aims to investigate the clinical significance of CD4+CD25+TNFR2+T cells in patients with lung cancer and the possible molecular mechanism of Jak-Stat pathway and NFAT-AP-1 pathway in regulating the function of Tregs. Therefore, it could provide more evidence for TNFR2 successfully identificating much more functionally Tregs.

调节性T细胞（Regulatory T cells, Treg）是肿瘤免疫逃逸的主要机制之一。新的肿瘤治疗策略应在刺激效应性T细胞的同时清除Treg。已知75%-100%的小鼠肿瘤浸润Treg表达TNFR2，且CD4+TNFR2+T细胞亚群较CD4+CD25+T细胞亚群的抑制活性高出近4倍。去除TNFR2+Treg同时联合化疗能够彻底消除肿瘤。正常人外周血Treg也高表达TNFR2，并在Treg免疫抑制活性中起关键作用。本课题组前期实验结果显示TNFR2在肺癌患者外周血Treg中高表达，体外肺癌细胞系负载后CD4+CD25-T细胞Foxp3和TNFR2表达同步提高。本项目拟探讨Treg中TNFR2和Foxp3的关系及TNF-TNFR2通路在诱导Treg分化中可能的作用机制，从而为TNFR2成为功能性Treg关键性表面标志提供理论依据。

调节性T细胞（Regulatory T cells, Treg）是肿瘤免疫逃逸的主要机制之一。.研究显示在小鼠和健康志愿者中，TNFR2+Treg代表着最有抑制功能的Treg细胞亚群。本研究探讨了肺癌患者外周血中Treg表面TNFR2的表达与foxp3的关系，证实在肺癌外周血CD4+T细胞亚群中，Tregs中TNFR2的表达明显高于Tconvs，TNFR2+Tregs具有增殖表型和免疫抑制表型。肺癌患者外周血来源的TNFR2+Tregs可有效抑制CD8+T细胞的增殖和IFN-γ分泌，并且较TNFR2-Tregs细胞具有更强的免疫抑制作用。肺癌病人外周血TNFR2+Tregs细胞的比例，与淋巴结转移、远处转移及临床分期具有明显的相关性。基于TNFR2+Tregs的功能特性及其与临床肺癌转移分期的关系，TNFR2可以辅助临床诊断肺癌晚期转移，并有望作为针对Tregs靶向治疗的靶标。