RRAD促进免疫应答调控PD-1单抗治疗非小细胞肺癌敏感性的作用及机制研究

PD-1单抗免疫疗法已成为肺癌治疗的重要手段。然而，PD-1单抗目前仍无理想的疗效相关分子生物标志物，且关于PD-1单抗耐药的机制知之甚少。本课题组前期研究发现，在接受PD-1单抗治疗的非小细胞肺癌患者中，治疗后进展组RRAD基因表达水平显著低于未进展组，且RRAD低表达组患者的总生存期显著低于高表达组患者。RRAD可抑制有氧糖酵解并减少乳酸生成。肿瘤细胞通过有氧糖酵解产生乳酸，从而抑制树突状细胞成熟及T淋巴细胞增殖活化。由此推测，RRAD基因高表达减少乳酸生成，促进树突状细胞成熟，活化T淋巴细胞而提高PD-1单抗的疗效；RRAD低表达引起免疫细胞功能及活化异常，导致PD-1耐药。课题拟进一步通过临床研究、细胞实验及动物模型，分析RRAD在PD-1单抗治疗中的免疫调节机制，并探索不同的免疫联合治疗模式。研究结果将阐明PD-1单抗耐药新的分子机制，为肺癌治疗提供潜在的药物干预靶点。

Anti-PD-1 immunotherapy has become an important treatment option for lung cancer. However, there are still no ideal molecular biomarkers to predict the efficacy of anti-PD-1 immunotherapy. The mechanism of drug resistance is also unclear. Our previous study found RRAD gene expression in the progressive group of non-small cell lung cancer patients receiving anti-PD-1 immunotherapy was significantly lower than that in the non-progressive group. In addition, the overall survival of patients with low RRAD expression was significantly shorter than that of patients with high RRAD expression. Activated RRAD inhibits aerobic glycolysis and reduces lactic acid production. Lactic acid is produced by tumor cells through glycolysis, which inhibits dendritic cells maturation and T lymphocytes proliferation. Therefore, it is hypothesized that high RRAD expression reduces lactic acid production and promotes the maturation of dendritic cells. Mature dendritic cells further activate T lymphocytes, which enhances the efficacy of PD-1 inhibitors in non-small cell lung cancer. Whereas low expression of RRAD causes abnormal activation and dysfunction of immune cells, resulting in drug resistance of anti-PD-1 immunotherapy. This study intends to clarify the mechanism of RRAD in immunomodulation for anti-PD-1 therapy and explore combination immunotherapy through cell experiments and animal models. The new molecular mechanism of anti-PD-1 drug resistance may be found, which could provide potential drug targets for the treatment of lung cancer.