γδT细胞异质性介导微生境失衡促进大肠癌演进的关键机理

肿瘤浸润淋巴细胞异质性是大肠癌微环境研究的热点和难点，其核心成分-γδT细胞在肠道黏膜免疫中起关键作用。我们前期发现γδT细胞新亚群如γδT17、CD39+γδT细胞促进大肠癌进展而Vδ1 γδT细胞相反，提示γδT细胞异质性是大肠癌免疫微环境失衡的关键。我们还发现大肠癌相关肠道微生境失衡能重塑γδT细胞异质性。因此我们假设在大肠癌演进不同阶段，肠道微生境失衡激活γδT细胞，促进其向不同功能亚群极化，形成以γδT细胞异质性为特征的异常肿瘤免疫微环境，最终促进肿瘤进展。本项目拟通过构建人肿瘤组织γδT细胞全景图谱并明确其异质性调控大肠癌微环境的关键机制；探究γδT细胞异质性在大肠癌演进不同阶段的作用；解析肠道微生境失衡重塑γδT细胞异质性的机理及其干预策略；评价γδT细胞异质性的临床转化价值。项目的完成将填补γδT细胞异质性调控大肠癌演进的理论空白，也为探索肿瘤新型免疫治疗提供新思路和靶标。

Tumor infiltrating lymphocyte (TIL) heterogeneity is the spotlight and challenge in the research field of colorectal cancer microenvironment. As the key composition of TIL, γδT cells play a nonredundant role in intestinal mucosal immunity. We previously found that novel subsets of γδT cells including tumor-promoting γδT17 and CD39+γδT cells and tumor-controlling Vδ1 γδT cells, suggesting that γδT cell heterogeneity is a key participant in colorectal cancer immune microenvironment. We also found that intestinal microbiota dysbiosis can remodel γδT cell heterogeneity. Therefore, we hypothesized that during colorectal tumourigenesis and progression, intestinal microbiota dysbiosis activates γδT cells and dynamically regulates γδT cell heterogeneity, which forms a tumor-promoting immune microenvironment. Our project aims to build a landscape of γδT cells in human colorectal cancer and clarify the underlying regulatory mechanism of γδT cell heterogeneity in tumor microenvironment; to explore the role of γδT cell heterogeneity in tumourigenesis and progression of colorectal cancer; to analyze the key mechanism and intervention of γδT cell heterogeneity remodeling via microbiota dysbiosis ; to evaluate the clinical value of γδT cell heterogeneity. This project will fill research blank regarding the regulatory role and mechanism of γδT cell heterogeneity in colorectal cancer progression, and provide novel ideas and targets for exploring new cancer immunotherapy.