化疗介导的肿瘤新生抗原改变对胃癌PD-1抑制剂疗效的影响及机制研究

肿瘤新生抗原是在肿瘤突变基础上产生的能被免疫系统递呈和识别的特异性抗原，参与了免疫杀伤肿瘤细胞的重要环节。已证实肿瘤新生抗原的动态改变与免疫治疗PD-1抑制剂的疗效密切相关,高新生抗原负荷通常提示着更好的疗效；而化疗干预能引起肿瘤突变特征的变化进而介导肿瘤新生抗原的改变。我们前期在胃癌PDX模型上发现一批年轻型胃癌患者（≦45岁）对常规化疗反应差，其中经PD-L1阳性筛选的患者接受了PD-1抑制剂的治疗，但均表现出了原发耐药现象；而全外显子测序和新生抗原预测分析则提示年轻型胃癌患者组的肿瘤新生抗原负荷显著低于常见胃癌组（>50岁）。因此，本课题拟在已建立的PD-1抑制剂耐药模型上，通过化疗干预来介导胃癌新生抗原特征的改变（如增加新生抗原负荷等）；并进一步在免疫重建模型中探索上述改变对胃癌PD-1抑制剂疗效的影响及潜在机制，为克服PD-1抑制剂耐药提供新思路。

Tumor neoantigens are encoded by tumor-specific mutated genes, which can be presented and recognized by T cells. Meanwhile, tumor neoantigens play an important role in the immune killing of tumor cells. It has been demonstrated that the dynamic changes of tumor neoantigens will directly affect the efficacy of PD-1 inhibitors. Usually, high burden of tumor neoantigens indicates a better efficacy. Our previous study found that early-onset gastric cancer（≦45years old）had poor response to conventional chemotherapy in PDX models. Among these patients, some of the PD-L1-positive ones received PD-1 inhibitor treatment, but showing obvious primary drug resistance. Meanwhile, exon sequencing and neoantigens analysis suggested that early-onset gastric cancer patients had significantly lower neoantigens load than common ones（>50 years old）.This study aimed to explore the impact of chemotherapy on the dynamic changes of neoantigens in PD-1 drug-resistant PDX models; and further explore the impact of these dynamic changes of neoantigens on the sensitivity of PD-1 inhibitors in immune reconstruction models, which provides new ideas for overcoming the drug resistance of PD-1 inhibitors.