靶向CLDN18-ARHGAP融合突变在胃印戒细胞癌免疫治疗中的研究

胃印戒细胞癌是胃癌中恶性程度最高、预后最差的一种亚型，缺乏有效的治疗手段。肿瘤突变产生的新抗原所诱导的反应性T细胞是多种免疫治疗发挥作用的基石。CLDN18-ARHGAP融合突变是胃印戒细胞癌驱动基因之一，通过RhoA通路调控肿瘤发生发展。申请人前期研究发现CLDN18-ARHGAP融合突变具有免疫原性，并可激活免疫微环境，是免疫治疗的潜在受益人群，而RhoA通路抑制剂可以进一步增强免疫抗肿瘤效果。本项目拟以CLDN18-ARHGAP融合突变为靶点，免疫信息学工具预测、合成并鉴定具有免疫原性的CLDN18-ARHGAP融合突变新抗原肽，在细胞及动物水平评价CLDN18-ARHGAP融合突变反应性T细胞抗肿瘤作用。同时，深入研究CLDN18-ARHGAP融合突变通过RhoA通路关键因子调控肿瘤的具体作用机制，探讨免疫联合靶向治疗CLDN18-ARHGAP融合突变胃印戒细胞癌的新策略。

Gastric signet ring cell carcinoma (SRCC) is a subtype with poor prognosis of gastric adenocarcinoma. There are rare effective therapeutic drugs for SRCC. Neoantigen specific T cells targeting tumor mutations are the cornerstone of multiple immunotherapy strategies. CLDN18-ARHGAP fusion is one of the oncogene for gastric SRCC, regulating the formation and development of tumor by dysregulating RhoA pathway. Our previous study found neoantigen derived from CLDN18-ARHGAP was immunogenicity and could active immune microenvironment. Therefore, patients with CLDN18-ARHGAP fusion may benefit from immunotherapy. Additionally, inhibitors of RhoA pathway may further enhance the antitumor effect by immunotherapy. Based the information above, the present project is intended to provide a potential treatment to gastric SRCC with CLDN18-ARHGAP fusion. We plan to predict CLDN18-ARHGAP fusion specific neoantigens. Neoantigen specific peptides will be synthesized and evaluated. Neoantigen specific T cells will be cultured and evaluated for its anticancer effect of them in vitro and in vivo. Moreover, the mechanism of how CLDN18-ARHGAP fusion regulates RhoA pathway will also be studied to provide a new strategy of immunotherapy combining targeted therapy in gastric SRCC.