GSK-3β调控Tscm细胞分化在胃癌中的作用及机制研究

记忆性干细胞样T细胞（Tscm）是一种新型记忆性T细胞亚群，能够自我更新，具有多向分化潜能，可能成为免疫治疗肿瘤的新方向。前期研究发现，胃癌病人外周血中Tscm增高，并在TNM分期中呈下降趋势；荷瘤模型中，过继Tscm可抑制肿瘤生长；提示Tscm发挥免疫保护作用。研究还发现，抑制GSK-3β通过促进Tscm分化及上调FasL表达，从而增强其细胞毒性作用。本项目以GSK3β-FasL为研究对象，首先，在细胞及荷瘤模型中研究GSK-3β及FasL对Tscm分化及功能的调控；然后，通过ChIP，验证抑制GSK-3β促进FasL表达的分子机制；最后，临床标本验证GSK-3β对FasL的表达以及Tscm功能的调控；关联临床资料，分析三者在胃癌进展中的临床意义。明确GSK-3β调控Tscm分化而发挥保护的机制，将使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。

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 accumulated in peripheral blood of gastric cancer (GC) patients and decreased with disease progression; in addition, injection of GSK-3β inhibitor in Tscm transferred Rag1-/- mice bearing fore stomach carcinoma increased tumor regression. Furthermore, a small molecule GSK-3β inhibitor, upregulated FasL expression, resulted in increased CD8+ cytotoxic T lymphocyte (CTL) function of Tscm. In the study, we intend to investigate: 1). The regulation of GSK-3β and FasL on Tscm differentiation and function in vitro and in tumor-bearing mouse model; 2). The molecular mechanism of FasL expression upregulation after GSK-3β inhibition by the use of ChIP assay; 3). Verify GSK-3β on the regulation of FasL expression and Tscm function in GC patient samples, and analyze the correlations with clinical data. Our study will identify GSK-3β as a regulator of FasL expression which promote Tscm cell differentiation, and demonstrate the applicability of GSK-3β inhibitor in the modulation anti-tumor immunity of Tscm cells in GC.