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

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.

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。

胃癌是全球性的，具有高发病率和高致死率的恶性肿瘤。肿瘤免疫一直伴随着胃癌的发生、发展和转归等疾病进程。CD8+T淋巴细胞免疫应答在机体抵抗胃癌中发挥了重要作用，但是胃癌病人外周血及胃癌微环境中CD8+T淋巴细胞的功能不清楚。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。本项目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；最后研究介导Tscm细胞分化及杀伤胃癌细胞的信号通路。本研究发现胃癌病人外周血中Tscm细胞明显增高，并且在TNM分期中呈逐渐下降趋势。抑制GSK-3β信号通路促进Tscm细胞表达FasL及T-bet，从而增强Tscm细胞毒性作用。在荷瘤模型中，Tscm细胞表现出较强的抗瘤功能，并且与GSK-3β信号通路介导的细胞分化密切相关。本项目明确GSK-3β信号通路调控Tscm分化而发挥保护的机制，使GSK-3β及Tscm可能成为新型的免疫调节手段用于治疗胃癌提供新的思路和理论支撑。