Wnt/β-catenin信号通路调控PD-L1促进非小细胞肺癌免疫逃逸的机制研究

Lung cancer is the highest mortality rate of malignant tumors, non-small-cell lung cancer accounted for 80% of lung cancer cases, PD-L1 antibody still has many side effects in the treatment of non-small-cell lung cancer. So it is essential to understand the mechanism of how PD-L1 was regulated by each signaling pathway in non-small-cell lung cancer. In the previous study, we found β-catenin and PD-L1 were highly correlated in non-small-cell lung cancer patient samples, so we overexpress β-catenin in non-small cell lung cancer cell lines H1299 and found that both mRNA levels and protein levels of PD-L1 were significantly increased . We found the binding site of TCF / LEF on the promoter of PD-L1. We demonstrated that β-catenin can bind directly to the PD-L1 promoter by Luciferase and ChIP experiments. The effect of Wnt/ β-catenin signaling pathway on PD-L1 and its effect on immune escape of non-small cell lung cancer were explained by cell model, mouse model and patient samples.

肺癌是死亡率最高的恶性肿瘤，而非小细胞肺癌占据肺癌病例的80%之多，PD-L1抗体在治疗肺癌时仍有着许多副作用，因此了解非小细胞肺癌中各个信号通路对PD-L1的调控机制对于PD-L1抗体在非小细胞肺癌治疗中的应用至关重要。在前期的相关研究中，我们发现非小细胞肺癌病人样本中β-catenin和PD-L1的表达高度相关，于是我们在非小细胞肺癌细胞系H1299中过表达β-catenin，PD-L1的mRNA水平和蛋白水平有着明显的增高。我们在PD-L1的启动子上找到了TCF/LEF的结合位点，我们通过Luciferase实验和ChIP实验证实了TCF4能够直接结合到PD-L1启动子上对其进行转录调控。本项目拟利用细胞模型、小鼠模型及其病人样本阐释Wnt/β-catenin信号通路对PD-L1的调控机制及其对非小细胞肺癌免疫逃逸的影响。