在肝癌期间,胆酸合成阻碍了瘤特异性T细胞反应
Siva Karthik Varanasi1, Dan Chen1, Yingluo Liu2
1NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
概括
在肝癌中改变胆酸 (BA) 合成可增强T细胞免疫力和免疫治疗反应. 调节BA,如乌尔索多西可酸, 显示改善癌症治疗的希望.
科学领域:
- 肝病学
- 免疫学
- 癌症新陈代谢
背景情况:
- 瘤微环境的代谢状态会影响癌症免疫力.
- 在肝癌免疫监测中,器官特异性代谢物 (如胆酸) 的作用尚不完全理解.
研究的目的:
- 研究胆汁酸对肝细胞癌 (HCC) 和抗瘤免疫力的影响.
- 探索调节胆酸合成或肝癌免疫治疗中的治疗潜力.
主要方法:
- 在人类和实验性肝癌模型中分析胆酸积累.
- 胆酸-CoA:氨基酸N-转移酶 (BAAT) 的遗传删除以抑制结合BA合成.
- 评估T细胞反应,瘤生长和对抗编程细胞死亡蛋白1 (抗PD-1) 治疗的反应.
- 对单个胆酸对CD8+T细胞功能的评价.
主要成果:
- 初级结合酸和二次结合酸的积累是肝癌的标志.
- 通过BAAT删除抑制BAA合成,增强了瘤特异性T细胞反应,并减少了瘤生长.
- 抑制BA合成的瘤对抗PD-1免疫疗法的敏感性增加.
- 不同的BA不同调节T细胞;初级BA诱导氧化应激,而石化酸通过ER应激损害T细胞功能,这种效应被ursodeoxycholic acid抵消.
结论:
- 胆汁酸代谢对肝癌的免疫微环境产生显著影响.
- 调节胆汁酸合成或饮食摄入量,特别是与酸,可以增强抗瘤免疫力和改善肝癌的免疫治疗结果.
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