肠道厌氧菌S.Moorei通过抑制AGK调节浸润性CD8+T细胞糖酵解增强直肠癌的辐射抵抗及机制

肠道细菌对肿瘤发生发展及治疗反应的调节是当前研究热点，但其与直肠癌辐射敏感性的关系尚无报道。我们前期发现：1）直肠癌组织中定植菌群与其辐射敏感性相关，辐射抵抗的癌组织中定植厌氧菌S.Moorei丰度显著高于敏感组；2）直肠癌组织中的浸润性CD8+T细胞在辐射抵抗组中匮乏而在敏感组中富集。研究又证实，CD8+T细胞中酰基甘油激酶（AGK）可通过促进糖酵解增强其自身增殖及免疫功能，而S.Moorei也被证实能够产生调节人体抗肿瘤免疫的硫化氢，且硫化氢可参与调控糖酵解。据此推测，S.Moorei代谢产物硫化氢可能作用于AGK，抑制CD8+T细胞的糖酵解及杀伤功能，进而增强直肠癌的辐射抵抗。本项目拟从分子、细胞和动物实验，旨在探究S.Moorei代谢产物硫化氢抑制AGK的生物学效应及机制。本项原创性研究开辟了肿瘤辐射敏感性调控领域一个新的研究方向，预期结果将为逆转直肠癌辐射抵抗提供新的思路和途径

The regulation of intestinal bacteria on tumor occurrence, development and treatment response is the current research focus, but the relationship between intestinal bacteria and radiosensitivity of rectal cancer has not been reported. We found that: 1) the colonization flora in rectal cancer tissue was related to its radiosensitivity, and the abundance of colonized anaerobes S.Moorei in radiation-resistant cancer tissue was significantly higher than that in sensitive group; 2) tumor infiltrating CD8+T cells in rectal cancer tissue were deficient in radiation resistance group and enriched in sensitive group. Studies have confirmed that acylglycerol kinase (AGK) in CD8+T cells can enhance its proliferation and immune function by promoting glycolysis, and S.Moorei has also been confirmed to produce H2S that regulates human anti-tumor immunity, and H2S can participate in the regulation of glycolysis. It is speculated that H2S, the metabolite of, S.Moorei, may inhibit the glycolysis and killing function of CD8+T cells by AGK, and then enhance the radiation resistance of rectal cancer. The purpose of this project is to explore the biological effect and mechanism of H2S, a metabolite of S.Moorei, on inhibiting AGK from molecular, cellular and animal experiments. This original study opens up a new research direction in the field of tumor radiosensitivity regulation, and the results will provide new ideas and approaches for reversing the radiation resistance of rectal cancer.