我们前期研究发现EGFR突变可上调肺癌PD-L1表达，但临床上EGFR突变肺癌对免疫治疗原发耐药，其机制仍不明。我们新发现EGFR突变肺癌微环境中Treg活化增加，CD8+ T细胞浸润减少。细胞实验发现EGFR突变导致肺癌TGF-β通路活化、上清液TGF-β1 mRNA增加，且激活TGF-β的关键蛋白GARP也表达上调。我们猜想，EGFR突变不仅通过上调PD-L1实现免疫逃逸，还可能通过转录上调TGF-β1和GARP，促进更多的TGF-β1在肿瘤微环境中产生和活化，从而全面活化Treg，协助肿瘤细胞多方位逃逸免疫杀伤。本项目将深入研究EGFR突变上调TGF-β1和GARP的分子机制，及其对Treg功能和抗PD1免疫治疗的影响。利用转基因小鼠模型探索如何逆转Treg介导的抗PD1免疫治疗原发耐药。本研究将揭示EGFR突变肺癌免疫治疗原发耐药的可能机制，为EGFR突变肺癌患者免疫治疗提供新思路

Our previous study showed that EGFR mutation could up-regulate the expression of PD-L1 in lung cancer. However, patients with EGFR mutant lung cancer are primarily resistant to immunotherapy, whose underlying mechanisms remain unknown. We recently found that the microenvironment of EGFR mutant lung cancer has increased activated Treg and less CD8+ T cell infiltration. Cell experiments indicate that EGFR mutation leads to activation of TGF-β pathway, increase TGF-β1 mRNA level in the supernate, and the TGF-β-activating protein GARP also was up-regulated. We hypothesize that EGFR mutation not only leads to immune escape by up-regulating PD-L1, but also can transcriptionally up-regulate TGF-β1 and GARP that leads to the production and activation of TGF-β1 in the tumor microenvironment. Collectively, these lead to the full-scale activation of Treg, which help tumor cells evade immune killing from multiple aspects. This project will comprehensively investigate the molecular mechanism of how EGFR mutation up-regulate TGF-β1 and GARP and its impact on the function of Treg, as well as the efficacy of anti-PD1 immunotherapy. Using transgenic mice model, we explore the ways to reverse the Treg-mediated primary resistance to anti-PD1 therapy. This study will unveil the possible mechanism of EGFR-mutation-induced primary resistance to immunotherapy in lung cancer and pave new ways for the immunotherapy of EGFR-mutant lung cancer.