我们前期研究发现EGFR突变可上调PD-L1表达，介导肺癌的免疫逃逸；PD-L1高表达可能参与了EGFR-TKIs耐药，但其具体机制未明。我们预实验发现p53基因变异合并EGFR突变后，PD-L1表达显著升高，并与EGFR-TKI原发和继发耐药相关。我们假设p53缺失和/或突变强化了EGFR突变介导的PD-L1上调，导致肺癌的免疫逃逸和EGFR-TKI耐药。本项目将在不同p53基因背景的肺癌细胞系中，研究p53（野生、缺失、突变）三种状态对EGFR基因介导的PD-L1调节的影响，阐明其分子机制，并通过肿瘤细胞与T细胞共培养体系及EGFR突变/p53缺失转基因小鼠模型，揭示p53和EGFR基因对免疫微环境及肺癌细胞活性的影响。本项目将首次研究癌基因和抑癌基因共同调节PD-L1的机制，为精准定位抗PD-1/PD-L1免疫治疗的获益人群和克服EGFR-TKIs耐药提供理论基础和实验依据。

Our previous study found that EGFR mutation could up-regulate the expression of programmed cell death ligand 1 (PD-L1) and mediate immune evasion of lung cancer; and high expression of PD-L1 may be involved in the drug resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), the detailed mechanisms of which remain unknown. Our preliminary experiments found that PD-L1 expression was remarkably over-expressed in the circumstance of p53 and EGFR co-alterations which also was associated with primary and secondary EGFR-TKIs resistance. We hypothesize that p53 loss and/or mutation amplifies the EGFR mutation-mediated PD-L1 up-regulation and leads to immune evasion and EGFR-TKIs resistance in lung cancer. In the project, we utilize lung cancer cell lines with different p53 gene status to investigate the impact of three status of p53 gene (wildtype, loss and mutation) on the EGFR-mediated PD-L1 expression and unveil its molecular mechanisms. We also try to reveal the influence of p53 and EGFR genes on immune microenvironment and viability of lung cancer cells with tumor cell and T cell co-culture system and EGFR-mutant/p53-loss transgenic mouse models. The project will for the first time investigate the regulation of PD-L1 by oncogene and tumor suppressor gene collectively and provide theoretical basis and experimental rationale for precisely determining the patients that might benefit from anti-PD-1/PD-L1 antibodies and overcoming EGFR-TKIs resistance.