EGFR-TKI重塑肿瘤微环境影响非小细胞肺癌PD-1/PD-L1抑制剂疗效的机制研究

晚期非小细胞肺癌（NSCLC）EGFR-TKI治疗后（耐药的）单药ɑPD-1/PD-L1临床疗效欠佳。课题组前期在两种转基因（EGFR L858R和EGFR 19DEL/T790M）原发性肺癌模型中发现，TKI处理后肿瘤微环境（TME）中M-MDSC和CCL2显著增加。结合既往研究，申请者提出“EGFR-TKI通过诱导肿瘤细胞高表达趋化因子，募集M-MDSC向TME浸润，进而影响ɑPD-1/PD-L1疗效”的科学假说。拟在前期工作基础上，通过已建立的小鼠模型和临床样本，进一步观察TKI治疗引起TME内免疫细胞浸润的改变；采用MDSC清除实验等，明确MDSC浸润对ɑPD-1/PD-L1治疗TKI耐药肿瘤疗效的影响；采用RNA-seq等实验，阐明TKI上调肿瘤细胞趋化因子，促进M-MDSC浸润的分子机制。本项目的顺利开展，对发展新型免疫联合策略治疗TKI耐药后人群具有重要的临床实践指导意义。

PD-1/PD-L1 inhibitors have a poor effect on patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC) after EGFR-TKI treatment (resistance). Our previous work showed that an increase of monocytic-myeloid derived suppressor cell (M-MDSC) and chemokine ligand 2 (CCL2) secretion was observed in the tumor microenvironment (TME) of both EGFR L858R and EGFR 19DEL/T790M genetic-engineered mouse lung cancer model after exposure to EGFR-TKI. According to the previous studies and our preliminary results, we postulate that EGFR-TKI could remodel the immune microenvironment via inducing M-MDSC accumulation in the TME of EGFR-mutant NSCLC through promoting chemokine secretion. Thus it could result in the impaired efficacy of PD-1/PD-L1 inhibitors after EGFR-TKI resistance. Based on these previous results, the current project will further investigate the change of immune cells in TME after EGFR-TKI treatment by using EGFR L858R and EGFR 19DEL/T790M genetic-engineered mouse lung cancer model and clinical samples. We will explore the effect of MDSC infiltration on PD-1/PD-L1 inhibitors after exposure to EGFR-TKI in EGFR-mutant NSCLC by using MDSC removal experiments, etc. Moreover, we aimed to clarify the specific cellular and molecular mechanisms of the up-regulation of chemokine and M-MDSC infiltration by using RNA-seq and so on. This project will provide important clues to guide the subsequent treatment and rational combined immunotherapy strategies after EGFR-TKI resistance.