基于单细胞测序技术在EGFR-L858R肺癌模型中探究如何提高“冷”肿瘤对免疫治疗的响应

在中国，肺癌是发病率和死亡率最高的癌症。肺癌中85%以上的患者是非小细胞肺癌，而东亚非小细胞肺癌患者中，约50%的患者携带EGFR突变。而占肺癌很大比例的携带EGFR突变的患者对免疫治疗的响应率极低。目前急需对于这一现象进行研究以提高此类病人的存活率。在对免疫检查点抑制剂不响应的携带EGFR突变的非小细胞肺癌患者中，CD8+浸润T细胞的数量明显低于有响应的患者。因此我们假设，携带EGFR突变的非小细胞肺癌患者的肿瘤微环境特征影响了免疫疗法的效果。..本项目模拟人类EGFRL858R驱动肺腺癌形成过程，用高通量单细胞测序技术研究肿瘤形成的不同时期，肿瘤细胞和免疫细胞的变化，深入分析肿瘤微环境中细胞间相互作用，以期更加全面的认识肿瘤形成和免疫逃避机制，发现与“冷”肿瘤免疫抑制相关的新细胞亚型和免疫抑制通路中的关键基因，并有望为临床治疗此类肺癌患者将“冷”肿瘤转化为“热”肿瘤提供可能的新靶点。

Lung cancer is the most common and deadly cancer in China. Above 85% of lung cancers are Non-Small Cell Lung Cancer (NSCLC). In East Asia, about 50% of the NSCLC patients carry EGFR mutation. Recent clinical research shows that lung cancer patients with EGFR mutations respond poorly to immunotherapies. To improve the survival rate of EGFR mutated patients, it is critical to understand the underlying mechanism of their lack of response. In NSCLC patients with EGFR mutations, the number of tumor-infiltrating CD8+ T cells is significantly higher in the patients responds to immunotherapies than the patients did not. We hypothesize that the tumor microenvironment in NSCLC with EGFR mutations suppresses the immune system in fighting cancer...We propose to study the cell composition of the tumor microenvironment during the different stages of the cancer development using a mutated human EGFR induced mouse lung cancer model and high-throughput single-cell RNA-seq technology. To better understand the immune-escape of EGFR induced lung cancer, we will further investigate the interactions among tumor cells and different types of immune cells. More importantly, we are interested in identifying a subpopulation of cells or a group of genes that are responsible for the immune suppression in the “cold” tumor microenvironment. Finally, we hope to discover potential new targets for clinical intervention to improve the survival of NSCLC patients by converting “cold” tumor to “hot” tumor.