肠道菌群来源的内生性乙醇通过抑制CD8+T细胞浸润促进结直肠癌免疫逃逸的机制研究

结直肠癌肿瘤微环境中CD8+T细胞的浸润数量普遍较少，是引发肿瘤免疫逃逸的主要原因。肠道菌群失衡与肿瘤免疫微生态的紊乱密切相关，但其机制仍不清楚。我们前期研究发现，肠道菌群来源的内生性乙醇，其产量与肿瘤微环境中CD8+T细胞的浸润数量呈高度负相关，且能导致趋化因子转录调控蛋白RUNX3失活，抑制肿瘤细胞表达CD8+T细胞相关趋化因子CXCL9。本项目将结合微生物学、分子病理学及分子生物学研究方法，通过体内外实验，首次揭示肠道菌群通过释放乙醇抑制CD8+T细胞浸润，促进结直肠癌免疫逃逸的作用与机制。基于肿瘤微环境中CD8+T细胞的浸润数量与患者PD-1治疗敏感性密切相关，我们还将探明内生性乙醇对结直肠癌PD-1治疗敏感性的影响作用。本研究不仅为进一步阐明肠道菌群失衡促进肿瘤免疫逃逸的分子机制提供可靠的证据，还为确立内生性乙醇作为改善结直肠癌患者PD-1治疗敏感性的干预靶点提供充分的科学依据。

The infiltration of CD8+T cells in the tumor microenvironment of colorectal cancer is generally low, which is the main cause of tumor immune escape. The imbalance of intestinal bacteria is closely related to the disorder of tumor immune microecology, but its mechanism is still not clear. Our previous studies have found that the output of intestinal bacteria derived endogenous ethanol is highly negatively correlated with the number of CD8+ T cells infiltrated in the tumor microenvironment, and can cause the inactivation of the chemokine transcriptional regulatory protein RUNX3, as well as inhibiting the expression of CD8+ T cell related chemokine CXCL9 in tumor cells. This project intends to explore the role and mechanism of the intestinal bacteria derived endogenous ethanol in reshaping the tumor immune microecology, which promote the immune escape of colorectal cancer, by using microbiology, molecular pathology and molecular biology research methods in vivo and in vitro experiments. Because the infiltration of CD8+T cells in the tumor microenvironment is also closely associated with the sensitivity of CRC patient to PD-1 treatment, we will also explore the effect of endogenous ethanol on the sensitivity of CRC patients to PD-1 treatment. This project not only provides a new scientific basis for elucidating the molecular mechanism of intestinal bacteria in promoting tumor immune escape, but also initially clarifies the possibility of intervention in endogenous ethanol production as an effective measure to improve the sensitivity of PD-1 treatment in CRC patients.