STK11突变调控PD-L1表达介导SMARCA4突变型肺癌抗PD-1/PD-L1免疫治疗原发耐药的机制研究

SMARCA4突变型NSCLC患者具有独特的临床病理特征。目前针对SMARCA4突变型NSCLC的治疗策略尚未开发。既往研究发现该类突变患者常伴随着较高的肿瘤突变负荷，理论上是免疫治疗的获益人群。然而我们前期研究发现并不是所有的SMARCA4突变患者都能从抗PD-1/PD-L1治疗中获益。基于前期结果，我们提出科学假说：STK11突变通过活化PI3K/AKT/mTOR信号通路，下调了SMARCA4突变型肺癌的PD-L1表达，进而导致免疫治疗原发耐药。本项目拟：1、阐明STK11突变对SMARCA4突变肺癌PD-L1表达的影响及其分子机制；2、探讨不同STK11和SMARCA4基因状态对免疫微环境及肿瘤细胞活性的影响，初步验证克服耐药的新策略；3、明确STK11基因突变对于SMARCA4突变型肺癌免疫治疗的预测价值。本项目有望优化SMARCA4/STK11共存突变患者的免疫治疗策略。

SMARCA4-mutant NSCLC patients have unique clinicopathological characteristics. At present, the treatment strategy for SMARCA4-mutant NSCLC has not been established. Our previous studies have found that patients with this type of mutation are often accompanied by a higher tumor mutation burden. Theoretically, they are the beneficiaries of immunotherapy. However, we found that not all patients with SMARCA4 mutation can benefit from anti-PD-1/PD-L1 treatment. Based on the previous results, we put forward a scientific hypothesis: STK11 mutation down-regulates the expression of PD-L1 in SMARCA4-mutant lung cancer by activating the PI3K/AKT/mTOR signaling pathway, leading to primary resistance to immunotherapy. This project intends to: 1. To clarify the effect and mechanism of STK11 mutation on PD-L1 expression in SMARCA4-mutant lung cancer; 2. To explore the influence of different STK11 and SMARCA4 gene mutation status on the immune microenvironment and tumor cell activity, and to verify the new strategy to overcome drug resistance; 3. To clarify the predictive value of STK11 gene mutation for immunotherapy of SMARCA4-mutant lung cancer. This project is expected to optimize immunotherapy strategies for lung cancer patients with coexisting mutations of SMARCA4/STK11.