脆弱拟杆菌诱导的GM-CSF激活CD116+T细胞在结直肠癌中的作用机制研究

GM-CSF在结肠癌中的作用机制尚不清楚。我们前期研究发现结直肠癌组织中脆弱拟杆菌、GM-CSF及CD4+T细胞均明显增高，且互为正相关。脆弱拟杆菌能促进肿瘤内细胞分泌GM-CSF；同时，组织中部分CD4+T细胞表达GM-CSF受体CD116，提示GM-CSF可能直接调控CD116+T细胞。基于此，本项目拟对结直肠癌微环境内脆弱拟杆菌—GM-CSF—CD116+T细胞调控轴进行深入研究。旨在①揭示脆弱拟杆菌促进细胞分泌GM-CSF的调控机制；②阐明T细胞表达CD116的机制；③明确GM-CSF通过CD116直接调控T细胞功能；④利用动物实验验证脆弱拟杆菌诱导的GM-CSF对CD116+T细胞的调控影响结直肠癌的发生发展。本项目将有助于从全新的角度揭示结直肠癌中肿瘤、肠道菌群及免疫系统的联系，为明确GM-CSF在结肠癌中的作用机制及探索靶向CD116+T细胞亚群的免疫治疗提供理论基础。

The function of GM-CSF in colorectal cancer is less clear. Previously, we found the increased load of Bacteroides fragilis accompanied with increased expression of GM-CSF and CD4+T cells in colorectal cancer. Furthermore, we revealed that Bacteroides fragilis were able to promote cells to secrete GM-CSF in tumors. Meanwhile, a population of CD4+T cells were identified to express GM-CSF receptor α chain (CD116) in colorectal cancer tissues, indicating the possibility of their direct interaction with GM-CSF. This finding challenged the current dogma that GM-CSF could regulate T cell function indirectly via myeloid cells. Therefore, we will further explore the role of axis among Bacteroides fragilis, GM-CSF and CD116+T cells in colorectal cancer. We will address (1) the mechanism of GM-CSF expression of cells induced by Bacteroides fragilis stimulation; (2) the principle of T cells to express CD116; (3) the biological function of CD116+T cells with GM-CSF stimulation; (4) the potential role of different CD116+T subsets stimulated by GM-CSF induced by Bacteroides fragilis in animal colorectal cancer model. This project will provide evidences to explain how tumors, microbiota and immune cells affect each other, which will benefit for our understanding for the mechanisms of colorectal cancer initiation and progression and may provide clues for potential new targets for tumor immunotherapy.