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

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.

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。

项目的背景：. 针对PD-L1/PD-1 通路的单抗在非小细胞肺癌的治疗中取得了显著的效果。但是，对于具有靶向驱动基因突变的如EGFR 突变或ALK 突变的肺癌患者，TKIs 耐药后抗PD-L1/PD-1单抗的有效率明显低于无驱动基因突变的患者，其内在的机制并不完全清楚。我们前期研究发现究发现PD-L1 表达在非小细胞肺癌与EGFR 突变状态相关，体外研究证明EGFR 突变激活下调主要组织相容性复合体MHC-I和MHC-II 类分子，而使用EGFR-TKIs 可以上调MHC-I 和MHC-II 类分子。.主要研究内容：.1).EGFR 对MHC-I/II 分子和PD-L1 的主动调控及其机制.2).IFN-γ对MHC-I/II 分子和PD-L1 适应性调控及其与EGFR 主动调控的关系.3).EGFR-TKIs 与抗PD-1 单抗联合应用的抗肿瘤效应与免疫相关肺炎.4).MHC-I/II、PD-L1 的表达、组织微环境免疫细胞与EGFR突变状态、抗PD-1免疫治疗疗效的相关性研究.重要结果，关键数据：. 通过体外研究我们发现EGFR配体EGF激活与EGFR突变激活均可正向上调PD-L1表达，负向下调MHC-I分子的表达。 IFN-γ可正向上调PD-L1、 MHC-I分子的表达。EGFR活化介导MHC-I分子的抑制与活化AKT/mTOR信号通路有关。EGFR-TKIs下调PD-L1表达，上调MHC-1分子。EGFR抑制通过PI3K/AKT/mTOR信号通路增加抗原加工和提呈系统相关蛋白PSMB8、PSMB9的表达，EGFR-TKIs和AKT/mTOR抑制剂通过STAT1/STAT3转录因子作用于抗原加工系统和抗原提呈系统，从而影响膜上MHC-I表达。通过临床数据研究发现TMB是抗PD-1免疫治疗疗效的正向预测标志物。肿瘤突变负荷TMB、EGFR/ERBB2的突变状态与免疫治疗疗效相关。抑癌基因如ITGA9及PLCD1等的缺失、免疫相关Chemokine Receptor（CCR）通路基因的缺失以及染色体3p缺失，均预示更差的免疫治疗效。.科学意义：. 揭示了EGFR突变肺癌患者免疫治疗疗效不佳在抗原呈递上存在缺陷的新机制，鉴定了多个预测肺癌抗PD-(L)1免疫治疗疗效的标志物，为克服免疫治疗耐药、提高免疫治疗疗效提供了理论与研究证据。