微生境失衡状态下γδT17细胞促进炎症性肠病癌变的作用机制

The Carcinogenesis of inflammatory Bowel Disease(IBD) has been associated with gut microhabitat disorder and chronic inflammation, while its mechanism is still unclear. Preliminary data has shown γδT17 cells play a role in some inflammatory diseases and tumors in animal models. In our previous investigation with human CRC, we uncovered that polarization of γδT17 cells by commensal bacteria plays a predominant role in human CRC progression. However, its role in human IBD and inflammation-gut microhabitat disorder-cancer sequential carcinogenesis of IBD remains unknown. our preliminary investigation with human IBD tissue showed γδT17 cells is the major IL-17-producing cells. Thereafter, we hypothesize that epithelial barrier disruption caused by gut microhabitat disorder facilitates bacterial translocation and accumulation of myeloid cell, which trigger γδT17 cell activation, thus inducing chronic inflammation and immunosuppression leading to IBD carcinogenesis. In the proposed study, we will systematically characterize the phenotype, function and polarization mechanism of γδT17 cells in human IBD tissue based on primary cell isolation and identification platform and IBD animal model. In addition, we will explore their roles in sequential carcinogenesis of IBD. We will also evaluate the efficacy of interventions targeting to γδT17 cells/IL-17A. The successful completion of this project will provide new insight into understanding the role of γδT17 cells in the immuno-regulatory mechanism of IBD carcinogenesis and provide novel potential therapeutics for CRC.

微生境失衡及慢性炎症与炎症性肠病（IBD）癌变存在密切联系，然而其确切机制不清。有研究显示γδT17细胞与多种炎症及肿瘤相关，我们先前研究提示细菌侵入通过以γδT17细胞为核心的调控机制促进人结直肠癌进展，然而γδT17细胞在人IBD及肠道炎症-微生境失衡-癌变序列中的作用机制尚无报道。课题组前期研究发现γδT17细胞是人IBD肠粘膜IL-17A的主要来源。故我们提出假说：微生态失衡引起细菌侵入，激活髓系细胞分泌γδT17细胞极化相关因子，促进肠道炎症及免疫抑制导致IBD癌变。本项目拟以原代细胞分离鉴定平台及IBD相关肠癌小鼠模型为基础，系统分析γδT17细胞在人IBD中的特征及极化机制，阐明其在IBD癌变序列中的作用及关键调控机制，探索靶向γδT17细胞/IL-17A干预IBD癌变的潜在价值。项目的完成可填补γδT17细胞在IBD癌变中的作用及机制理论研究的空白，为转化研究提供新思路。

本课题通过流式细胞术、微生物多样性分析、菌群移植等方法与技术，对γδT17细胞参与肠炎-微生境失衡-肿瘤的IBD癌变序列中的作用进行了深入研究。首先通过系统地鉴定IBD病变组织γδ17表型特征、分化相关表型，并研究IBD相关肠癌模型不同阶段γδ17细胞变化，确定γδ17细胞在IBD发展癌变过程中的重要性。通过微生物多样性分析、抗生素干预及菌群移植，确定了菌群紊乱与IBD癌变过程的相关性；进一步通过研究肠道浸润免疫细胞相互作用，探索了微生境失衡导致γδ17细胞变化从而促进IBD 癌变的可能性。综上所述，本研究为明确以γδT17细胞为核心的免疫调控轴在微生境失衡下IBD癌变中的作用机制奠定了坚实的工作基础。