cGAS-STING信号通路通过激活Galectin-9-TIM-3免疫检查点参与非小细胞肺癌免疫逃逸的机制研究

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a promising checkpoint. Our previous results showed that TIM-3 positivity was associated with earlier recurrence after surgery, and the prognosis of patients with high expression of cyclic GMP-AMP synthase (cGAS) was even worse among those with TIM-3 positive. Interestingly, activation of the cGAS-STING pathway in tumor cells can up-regulate the expression level of Galectin-9 (Gal-9, TIM-3 ligand); moreover, the expression of cGAS was positively correlated with Gal-9 in patients with non-small cell lung cancer (NSCLC). Hence, we proposed that cGAS-STING pathway mediate the immune evasion of lung cancer cells by boosting TIM-3 via the up-regulating of Gal-9 on lung cancer cells. In this project, lung cancer cells which transfected by lentivirus-mediated cGAS/cGAS inhibitor and xenograft mouse models will be used to observe the role and the mechanism of cGAS-STING pathway in immune evasion mediated by TIM-3. The project will not only elucidate the molecular mechanism of immune evasion mediated by TIM-3 in NSCLC, but also provide a new approach for immunotherapy strategies.

T细胞免疫球蛋白粘蛋白3（TIM-3）是一个极具临床治疗前景的免疫检查点。本课题组前期发现：TIM-3与肺癌术后复发相关，且TIM-3阳性肺癌患者中环鸟苷酸-腺苷酸合成酶（cGAS）高表达组预后更差；有趣的是，激活肿瘤细胞cGAS-STING通路可以上调TIM-3配体—半乳糖凝集素-9（Gal-9）的表达水平，且肺癌患者中cGAS与Gal-9的表达水平呈正相关。因此，我们推测：cGAS-STING通路通过上调肿瘤细胞表达Gal-9，进而激活TIM-3，实现免疫逃逸。本项目拟通过建立过表达和低表达cGAS肺癌细胞株和相应小鼠肿瘤模型，进一步明确cGAS-STING通路在肺癌细胞通过TIM-3免疫逃逸中的作用及其相关机制。本项目不仅能明确肺癌细胞通过TIM-3免疫逃逸的分子机制，更为临床免疫治疗策略的制定提供新思路。

T细胞免疫球蛋白粘蛋白3（TIM-3）是一个极具临床治疗前景的免疫检查点。本项目发现：TIM-3与肺癌术后复发相关，且TIM-3阳性肺癌患者中环鸟苷酸-腺苷酸合成酶（cGAS）高表达组预后更差；有趣的是，激活肿瘤细胞cGAS-STING通路可以上调TIM-3配体—半乳糖凝集素-9（Gal-9）的表达水平，且肺癌患者中cGAS与Gal-9的表达水平呈正相关。随后，我们又证实了Gal-9为cGAS-STING通路的下游作用靶点，抗TIM-3单抗只有在cGAS高表达LLC成瘤小鼠模型上有显著的抗肿瘤效果，而在cGAS敲除LLC成瘤小鼠模型上无抗肿瘤作用。因此，我们基本可以得出结论：cGAS-STING通路通过上调肿瘤细胞表达Gal-9，进而激活TIM-3，实现免疫逃逸。本项目不仅能明确肺癌细胞通过TIM-3免疫逃逸的分子机制，更为临床免疫治疗策略的制定提供新思路。