CircRHBDD1结合IGF2BP2上调PD-L1表达促进胃癌免疫逃逸的作用及机制研究

胃癌对免疫检查点抑制剂的总体应答率偏低，深入研究胃癌免疫逃逸机制有助于提高免疫治疗疗效。环状RNA在胃癌免疫逃逸中的作用目前仍不清楚。申请人前期通过高通量测序发现一个新的环状RNA circRHBDD1与胃癌PD-1单抗疗效相关，敲低circRHBDD1能抑制胃癌细胞免疫逃逸；进一步研究提示circRHBDD1可能与IGF2BP2结合，并且IGF2BP2介导的m6A修饰能增加PD-L1 mRNA稳定性。据此我们提出假说：circRHBDD1通过直接结合IGF2BP2，介导PD-L1 m6A修饰并上调PD-L1表达，从而促进胃癌免疫逃逸。本项目拟从临床、体外和体内层面，通过RIP、EMSA和miCLIP-seq等技术探讨circRHBDD1通过IGF2BP2/PD-L1轴促进胃癌免疫逃逸的具体分子机制，从环状RNA这个新视角为筛选胃癌免疫治疗优势人群、寻找免疫联合治疗靶点提供新策略。

The response rate of gastric cancer to immune checkpoint inhibitors is relatively low. Elucidating the mechanisms underlying immune escape of gastric cancer contributes to enhancing the efficacy of immunotherapy. The involvement of circular RNAs in gastric cancer immune escape remains obscure. We used high-throughput sequencing technologies and found that circRHBDD1, a novel circular RNA, was correlated with the response to anti-PD-1 treatment. CircRHBDD1 knockdown suppressed the immune escape of gastric cancer cells. Further investigation suggested that circRHBDD1 may interact with IGF2BP2, and N6-methyladenosine modification mediated by IGF2BP2 could augment PD-L1 mRNA stability. We here hypothesize that circRHBDD1 may mediate PD-L1 N6-methyladenosine modification and promote the expression level of PD-L1 through directly binding to IGF2BP2, thus facilitating immune escape of gastric cancer. Based on the clinical data, in vitro and in vivo experiments, this project aims to explore the molecular mechanisms of circRHBDD1-regulated IGF2BP2/PD-L1 axis in gastric cancer immune escape using RIP, EMSA and miCLIP-seq technologies. This study may provide a novel strategy for selecting gastric cancer patients who might preferentially benefit from immunotherapy and discovering molecular target for combined immunotherapy from the new perspective of circular RNA.