致癌关键功能菌群-pDCs轴在胃癌微环境内的免疫抑制作用研究

致癌关键功能菌群和浆细胞样树突状细胞（pDCs）介导的免疫抑制是胃癌发生发展的两个关键因素，但致癌关键功能菌群与pDCs之间是否存在交互作用并参与胃癌微环境内免疫抑制的机制依然未知。我们前期研究证实幽门螺杆菌、卡普瑞普氏菌、单行拟杆菌构成的致癌关键功能菌群与胃癌微环境内pDCs浸润密切关联。我们推测致癌关键功能菌群-pDCs轴通过短链脂肪酸(SCFAs)-mTOR信号转导通路调控胃癌微环境的免疫抑制，进而参与胃癌的发生发展。本项目利用悉生动物及条件性剔除pDCs等技术，采用宏基因组学、UPLC-MS代谢组学、生物信息学、分子免疫学等方法，在临床样本、动物、细胞水平进行研究，解析致癌关键功能菌群-pDCs轴是介导胃癌微环境免疫抑制的新途径，揭示SCFAs-mTOR信号转导通路是影响胃癌免疫抑制的分子机制，为开发基于致癌关键功能菌群-pDCs轴为靶点的胃癌防治新策略提供理论依据和实验基础。

Key carcinogenic functional microbiota and the immunosuppression mediated by plasmacytoid dendritic cells (pDCs) are the two key factors in the carcinogenesis and tumor progression of gastric cancer. However, it remains unclear whether there is interplay between key carcinogenic functional microbiota and pDCs in gastric cancer. Furthermore, the mechanisms of this interplay involved in the immunosuppressive microenvironment of gastric cancer are still unexplored. In our previous studies, it has been confirmed that the key carcinogenic functional microbiota, which consists of Helicobacter pylori, Prevotella copri and Bacteroides uniformis, is closely related to the infiltration of pDCs in the microenvironment of gastric cancer. We speculate that the key carcinogenic functional microbiota-pDCs axis mediates the immunosuppression of gastric cancer microenvironment through signal transduction pathway of short-chain fatty acids (SCFAs)-mTOR, then participating in the carcinogenesis and tumor progression of gastric cancer. Using such techniques as monoxenic and trixenic animal, conditional deletion of pDCs, etc. and applying to metagenomics, UPLC-MS metabolomics, bioinformatics, molecular immunology, etc., this project conducts research at the clinical samples, animal, and cell culture to explore whether key carcinogenic functional microbiota-pDCs axis is an important immunological mechanism for mediating immunosuppressive tumor microenvironment in gastric cancer. Furthermore, this project will also reveal whether the SCFAs-mTOR signal transduction pathway, which is utilized by key carcinogenic functional microbiota-pDCs axis, is an important pathway affecting the immunosuppression of gastric cancer. Generally, this project would provide theoretical and experimental evidence for the development of new strategies for prevention and treatment of gastric cancer based on key carcinogenic functional microbiota-pDCs axis.