抑制胃癌细胞糖酵解调控PD-L1联合免疫治疗的研究

进展期胃癌目前治疗效果有限，亟待寻求新的方法。有氧糖酵解是肿瘤细胞的重要特征，但单独抑制糖酵解在临床运用并未取得预期疗效。前期实验发现抑制糖酵解可上调PD-L1表达同时升高乙酰辅酶A，而乙酰辅酶A是蛋白质乙酰化修饰底物。我们已发表研究显示PD-L1启动子区组蛋白H3K9位点乙酰化与胃癌细胞PD-L1表达密切相关。另外，PD-L1表达水平是免疫治疗反应性指标，且上调肿瘤细胞PD-L1可增强免疫治疗效果。据此提出假设：抑制糖酵解通过升高乙酰辅酶A，增强H3K9乙酰化以促进胃癌细胞PD-L1表达，联合PD-1/PD-L1阻断可有效治疗胃癌。本项目通过细胞和动物实验及临床标本检测等来探索胃癌糖酵解抑制与PD-L1表达关系和分子调控机制以及与免疫治疗的联合作用，从而为进展期胃癌的治疗提供新的思路和方法。

The whole therapeutic efficacies for advanced gastric cancer is unfavorable and it is urgent to find a new measure. Aerobic glycolysis is a hallmarker of tumor cells. Our primary data showed that inhibition of glycolysis up-regulated the expression of PD-L1 and increased the intracellular acetyl-CoA level, which is the substrate for acetylation modification of proteins. Our previous results demonstrated that the acetylation of histone 3 in K9 site in the promoter regions of PD-L1 was correlated to the expression of PD-L1 in gastric cancer cells. In addition, the expression level of PD-L1 is an indicator of immunotherapy responsiveness, and up-regulation of PD-L1 in tumor cells could enhance the immunotherapy efficacy. Therefore, we made the hypothesis that inhibition of glycolysis could promote the expression of PD-L1 in gastric cancer cells by increasing acetyl-CoA and enhancing the acetylation of H3K9, and the combination of glycolysis inhibition and PD-1/PD-L1 blockade could effectively cure the gastric cancer. This project would reveal the relationship between glycolysis inhibition and PD-L1 expression in gastric cancer and the molecular mechanisms of the regulation as well as the combination efficacy of glycolysis inhibition and immunotherapy in cell-level and animal-level experiments and clinical specimen testings. Our study would provide new ideas and approaches for the treatment of advanced gastric cancer.