基于“扶正祛邪”理论配伍黄芪甲苷与苦参碱双靶向调控4-1BBL/Fas通路干预肿瘤微环境增强肺癌抗PD-1/PD-L1治疗的机制

肺癌是人类最常见的恶性肿瘤，在我国乃至全世界，其发病率和死亡率均居首位。当前免疫检查点抑制剂已成为肺癌的主要治疗手段，因肿瘤微环境免疫功能的缺失，导致无应答和耐药发生率较高，严重制约了免疫治疗在临床中的应用。根据“扶正祛邪”理论我们将黄芪甲苷和苦参碱配伍，基于小鼠模型实验和少量临床试验，我们发现能提高抗PD-1/PD-L1治疗的应答率和延缓耐药。故我们推测黄芪甲苷与苦参碱二药配伍存在协同作用，有利于克服某一信号途径或靶点存在的缺陷。本项目基于临床观察、前期实验和文献检索线索的基础上，拟通过验证黄芪甲苷与苦参碱配伍调节4-1BBL/Fas双信号通路在肿瘤免疫微环境中的作用，以及与免疫治疗手段联合的效果验证，采用肺癌小鼠模型构建和流式细胞术等方法，深入研究肿瘤微环境所介导的免疫机制，在临床、细胞和动物水平阐明中药防治肿瘤的机制，力图增强肺癌抗PD-1/PD-L1治疗的效能。

Lung cancer is the most common malignant tumor of human beings. Both its morbidity and mortality rank the first in China and even around the world. At present, immune checkpoint inhibitors has become the main treatment for lung cancer. However, due to the immune dysfunction and complexity of tumor microenvironment, the incidence of non response and drug resistance is relatively high, which seriously restricts the application of immunotherapy in clinical. According to the theory of "strengthening vital qi to eliminatepathogenic factors", we found that Astragaloside and Matrine could improve the response rate of anti PD-1/PD-L1 therapy and postpone drug resistance from animal experiements and small sample size of clinical studies. Therefore, we speculate that the synergistic effect of Astragaloside and Matrineis beneficial to overcome the defects in a certain signal pathway or target. On the basis of clinical observations, preliminary experiments and literature review, this project intends to explore the effect of Astragaloside combined with Matrine on 4-1BBL/Fas pathway in tumor immune microenvironment, and its combination treatment with immunotherapy. By adopting lung cancer mouse model construction, flow cytometry and etc., the immune mechanism mediated by tumor microenvironment was studied in depth. We aimed to figure out the detailed immune mechanism how traditional Chinese medicine(TCM) prevents and treats tumor at clinical level, celluar level and animal level. in order to improve the efficacy of anti PD-1/PD-L1 therapy in lung cancer.