CD155/TIGIT调控Tregs分化参与胃癌免疫逃逸的分子机制研究

Tregs plays crucial role in promoting the formation of immunosuppressive tumor microenvironment (TME) and the subsequent immune escape of gastric cancer by inhibiting T-cell anti-tumor immune activity. Our preliminary study showed that gastric cancer cells inhibited T cell glycolysis through CD155/TIGIT while fatty acid oxidation was increased in CD4+ TIGIT+ T cells. As LKB1-AMPK signal participated in the regulation of fatty acid oxidation and Treg differentiation, in combination with our pre-experiment results, we presumed that in tumor microenvironment the gastric cancer cells would activate LKB1-AMPK signal to promote the energy metabolism shifting towards fatty acid oxidation in CD4 T cell and further induce CD4 T cell differentiation into Tregs. Therefore, this study intends to establish a gastric cancer cells-CD4 T cells co-culture model, CD4 T cells TIGIT and LKB1 conditional knockout mice as well as patient-derived xenograft (PDX) tumor-bearing mice model, and adopting these models to clarify the mechanism of which the gastric cancer cells participated in the immune escape of gastric cancer that by regulating fatty acid oxidation of CD4 T cells via CD155/TIGIT regulating LKB1-AMPK signal to promote Treg differentiation. The implementation of this study will potentially provide a new target for gastric cancer management.

调节性T细胞（Tregs）通过抑制T细胞抗肿瘤免疫反应促进肿瘤免疫抑制状态形成，在胃癌免疫逃逸过程中扮演了关键角色。我们前期研究显示胃癌细胞通过CD155/TIGIT抑制T细胞糖酵解，且CD4+/TIGIT+T细胞脂肪酸氧化代谢活跃。鉴于LKB1-AMPK对脂肪酸氧化及Tregs分化的调控作用，结合预实验结果，我们推测：肿瘤微环境中，胃癌细胞通过CD155/TIGIT激活LKB1-AMPK信号促使CD4T细胞能量代谢向脂肪酸氧化转化，进而诱导CD4T细胞向Tregs分化。本研究拟建立胃癌细胞株和T细胞共培养模型、CD4T细胞特异TIGIT和/或LKB1条件敲除小鼠、人源化小鼠荷瘤模型，并在这些模型上通过相关信号通路的调节、体内干预等实验研究阐明胃癌细胞通过CD155/TIGIT激活相关信号通路调控Tregs分化参与胃癌免疫逃逸的机制，有望为改善胃癌患者的预后提供治疗新靶点和理论依据。

本项目研究了CD155/TIGIT调控Tregs分化参与胃癌免疫逃逸的分子机制。研究结果提示：TIGIT、PD-1和CD39等免疫抑制信号在胃癌肿瘤微环境的组织驻留记忆T细胞（tissue-resident memory T cells，Trm）中高表达，并代表肿瘤反应性浸润淋巴细胞（TIL）。进一步研究发现：脂肪酸氧化调控胃癌中CD8 +Trm的存活和抗肿瘤功能，靶向PD-L1信号转导可抑制胃癌细胞摄取脂肪酸并促进Trm细胞对脂肪酸的摄取，从而促进的Trm细胞的存活。课题组同时在PDX模型上验证了TIGIT高表达的Trm的抗肿瘤免疫反应机制，发现阻断PD-L1信号可显著增强CD103高表达Trm的细胞毒性作用。可见，脂肪酸氧化的重编程调控可拮抗TIGIT等免疫抑制信号并延长Trm细胞的寿命；而免疫检查点抑制剂的治疗可显著改善Trm细胞内脂肪酸氧化代谢能力，从而增强Trm细胞的抗肿瘤功能，并抑制肿瘤细胞的转移播散，具有一定的应用前景。此外，肿瘤微环境调控的相关分子机制错综复杂，除了免疫逃逸，肿瘤细胞的转移也与细胞迁移、侵袭、上皮间质转化以及耐药调控有关。课题组进一步在表观遗传学方面探索了肿瘤信号转导及肿瘤代谢引起肿瘤耐药及转移的机制并取得了一系列成果。并且，课题组设计制备了针对性调控肿瘤微环境的纳米颗粒体系，以及基于TACE治疗针对胃癌及肝转移的的温敏相变控释栓塞微球并进行了初步疗效评估，为了临床转化奠定了基础。综上所述，本项目深入探索了CD155/TIGIT在胃癌中的功能及相关分子机制，并研发了一系列针对性纳米载体和栓塞微球，为提高胃癌的疗效提供了新的思路和科学依据。