研究证实驱动基因可通过上调PD-L1介导肿瘤的免疫逃逸，抑癌基因p53则能加强宿主的免疫监视。但是，p53基因状态对癌基因介导的免疫调控的影响尚不清楚。我们前期研究发现非小细胞肺癌（NSCLC）ALK基因融合可通过p-ERK及p-AKT上调PD-L1。进一步研究发现，p53基因与ALK基因共同影响了肿瘤组织PD-L1的表达水平。预实验发现野生型p53可负性调节PD-L1的表达，突变型p53则上调PD-L1的表达。基于此，本项目将在不同p53基因背景的肺癌细胞系中，研究p53野生型、缺失、突变型三种状态对ALK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细胞共培养揭示p53和ALK对免疫功能及NSCLC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提供理论基础和实验依据。

Driver genes were reported to mediate immune escape of tumor by up-regulating PD-L1 expression while the tumor suppressor gene p53 could enhance the immune surveillance of the host. However, how the p53 gene status influence the immune modulation by oncogenes is poorly understood. We have previously shown that ALK fusion gene could up-regulate PD-L1 via p-ERK and p-ALK in non-small-cell lung carcinoma (NSCLC). We further found that p53 and ALK status together influence the expression level of PD-L1 in NSCLC specimens. Preliminary experiments showed that wild type p53 down-regulates while mutant p53 up-regulates PD-L1. Based on these, we try to study the impact of three different statuses of p53 gene, including wild-type, mutant and loss, on the regulation of PD-L1 by ALK and reveal its mechanisms. Also, we investigate how p53 and ALK together affect the immune function and viability of NSCLC cells. This project will for the first time study the combing effects of oncogene and tumor suppressor gene on PD-L1 regulation and provide theoretical and experimental bases for precisely targeting the benefiting patients from anti-PD-1/PD-L1 immune therapies.