肠道菌群来源的硫酸吲哚酚靶向调控肝癌微环境CD8+TRM细胞免疫耗竭的机制研究

肝细胞癌的发生发展与肿瘤微环境密切相关，免疫细胞及其信号网络异常可以促进肿瘤免疫逃逸。TRM是一群新近发现的具有组织驻留特征的免疫记忆性T细胞，但其在肿瘤中的作用机制尚不明确。我们前期发现肝癌肠道菌群丰度及其代谢物含量种类显著变化，且与单细胞测序鉴定的一组在肝癌组织中明显富集的新型CD8+TRM亚群免疫耗竭特征形成密切相关。本项目拟进一步探讨肝癌微环境中CD8+TRM细胞免疫特征、信号网络的组成及参与肿瘤免疫逃逸的效应功能；明确肠道菌群来源的代谢物硫酸吲哚酚经ABC转运蛋白进入CD8+TRM细胞后，抑制线粒体功能上调TOX导致免疫耗竭的调控机制；并利用临床组织样本分析验证肠道菌群介导的硫酸吲哚酚调控CD8+TRM耗竭特征影响免疫抑制微环境与肿瘤进展转移的关系。本项目的实施将有助于揭示肝癌发生发展与肠道微生态、免疫耗竭的互作新机制，为寻找有效的临床靶标及免疫治疗策略提供新思路。

The occurrence and development of hepatocellular carcinoma is closely related to the tumor microenvironment. Abnormal immune cells and their signaling networks can promote immune escape. TRM is a group of newly discovered immune memory T cells with tissue retention characteristics, but its role in tumors is still unclear. Previously we found that the abundance and its metabolites of intestinal microflora are significantly changed in HCC patients. And by single-cell sequencing, they were found closely related to the immune exhaustion characteristics of a group of new CD8 + TRM subpopulation that was significantly enriched in liver cancer tissue. This project intends to further explore the immune characteristics of CD8+TRM cells in the liver cancer microenvironment, the composition of the signal network, and their effective function to initiate tumor immune escape. We will investigate the mechanism of indole sulphate metabolite derived from the intestinal flora entering the CD8+TRM cells via the ABC transporter, Inhibiting mitochondrial function and up-regulating TOX which leads to immune exhaustion. Then, we will carry on clinical samples analysis to verify the intestinal flora-mediated indole sulfate regulation of CD8 + TRM exhaustion characteristics which affect the immunosuppressive microenvironment and tumor progression and metastasis. The implementation of this project will help to reveal the new interaction mechanism between HCC development, intestinal microecology and immune exhaustion, and provide new ideas for finding effective clinical targets and immunotherapy strategies.