EGFR对MHC-I/II分子和PD-L1的调控在肺癌免疫逃逸中的作用及免疫治疗策略研究

免疫治疗在肺癌领域取得了巨大成功，但EGFR突变的肺癌对抗PD-L1/PD-1高度抵抗，机制仍不清楚。我们已报道EGFR突变与PD-L1表达相关，EGFR下游信号活化参与PD-L1的调控。我们新发现EGFR突变激活抑制主要组织相容性复合体MHC-I、MHC-II的表达，EGFR-TKIs能上调MHC-I、MHC-II，并且与IFN-γ具有显著的协同效应。我们将深入研究：EGFR突变激活对MHC-I/MHC-II、PD-L1的主动调控与IFN-γ介导的适应性调控及其相互作用；EGFR-TKIs与抗PD-1联合治疗的抗肿瘤效应和免疫相关肺炎；最后通过临床标本验证MHC-I/MHC-II、PD-L1、淋巴细胞浸润与EGFR突变状态及抗PD-L1/PD-1治疗疗效的关系。本研究将揭示EGFR突变肺癌免疫治疗抵抗的可能机制，探索联合治疗的潜在获益与风险，为EGFR突变肺癌免疫治疗提供新的策略与思路。

Immunotherapy has made great success in lung cancer. However, patients with EGFR mutations are resistant to anti-PD-L1/PD-1 treatment. The detailed mechanism is largely unknown. We have previously reported that mutant EGFR was associated with PD-L1 expression. EGFR and its downstream signaling pathways were involved in the up-regulation of PD-L1. Recently, we found that activated EGFR with mutant EGFR could suppress the Major histocompatibility complex class I and class II (MHC-I, MHC-II). EGFR-TKIs could up-regulate MHC-1 and MHC-II, which was synergetic with IFN-γ significantly. We will focus on the following studies in this project：EGFR mediated regulation of MHC-I/II and PD-L1 by constitutive oncogenic signaling, IFN-γ mediated adaptive regulation and the interaction between the two regulation mechanisms; the anti-cancer effects and immune-related pneumonia under the combination treatment of EGFR-TKIs and anti-PD-1 antibody; the association of MHC-I/II and PD-L1 expression, tumor-infiltrating lymphocytes (TIL) with EGFR mutation status and response rates to PD-1 pathway blockade in non-small cell lung cancer. Our study will reveal the mechanisms why EGFR mutations are associated with low response to PD-1 pathway blockade. Besides, we will explore the potential benefits and risks with EGFR-TKIs and PD-1 pathway blockade combinations, which will provide novel strategies and ideas for non-small cell lung cancer patients with mutant EGFR.