胃癌外周血中Tscm细胞的分化、趋化及在胃癌免疫中的前瞻性研究

记忆性干细胞样T细胞（Tscm细胞）作为一种新的记忆性T细胞亚群，具有干细胞样特征，能够自我更新，具有多向分化潜能，可能成为过继性免疫治疗肿瘤的新方向。课题组前期研究发现，胃癌病人外周血中存在一群Tscm细胞，且显著高于正常人；在胃癌荷瘤模型中，Tscm细胞应答与肿瘤都呈现出先增高，然后达峰值，最后消退的动态过程；结合文献报道，我们推断Tscm细胞具有抗胃癌的作用，但机制尚不清楚。本项目拟通过细胞分选、Transwell、胃癌荷瘤模型、过继转移等手段，首先分析胃癌病人外周血中Tscm细胞的应答特征及在胃癌中的临床意义；其次探讨Tscm细胞分化为效应性T细胞，趋化迁移到胃癌微环境，杀伤胃癌细胞的机制；最后研究mTOR-FOXO1信号通路在介导Tscm细胞分化及杀伤胃癌细胞中的作用。本项目将为阐明胃癌病人外周血记忆性T细胞抗胃癌机制提供新的理论依据，对胃癌的免疫防治具有重要指导和临床应用价值。

T memory stem cell (Tscm) was identified as a new subunit of memory T cells, which is capable of massive proliferation and indefinite persistence. Tscm could be a potential therapeutic T cells for cancer immunotherapy. Previously, we found that Tscm was increased in peripheral blood of gastric cancer patients, and was significant higher than in health donor; in addition, Tscm response was consistent with tumor regression in tumor-bearing mouse model, which suggested that Tscm might be involved in the anti-tumor effect in gastric cancer. However, the underlying mechanism of the anti-tumor effect of Tscm is unknown. Thus, we intend to investigate: 1) The clinical significance of Tscm in peripheral blood of gastric cancer; 2) How Tscm differentiate into effector T cells, migrate into tumor microenvironment, and exert the anti-tumor effect in gastric cancer; 3) mTOR-FOXO1 signal pathway in the regulation of anti-tumor effect of Tscm, in terms of cell sorting, cell coculture, shRNA, tumor-bearing mouse model establishment and adoptive transfer. This study may provide new experimental evidence for the anti-tumor mechanism of memory T cells in peripheral blood of gastric cancer, and the identification of Tscm population is of direct relevance to the design of vaccines and T-cell therapies.