近日，美国索尔克生物研究所
据了解，癌症的代谢景观在很大程度上影响抗肿瘤免疫，然而，如何在肿瘤微环境中，特定器官的代谢物影响免疫监视仍不清楚。
研究人员发现，初级结合型和次级胆汁酸（BA）的积累，是人类肝细胞癌和实验性肝癌模型的代谢特征。通过删除胆汁酸结合酶胆汁酸-CoA:氨基酸N-酰基转移酶（BAAT），抑制肝细胞中结合型胆汁酸的合成，可以增强肿瘤特异性T细胞反应，减少肿瘤生长，并使肿瘤对抗程序性细胞死亡蛋白1（抗PD-1）免疫疗法更敏感。
此外，不同的胆汁酸对CD8+ T细胞的调节作用不同。初级胆汁酸诱导氧化应激，而次级胆汁酸石胆酸则通过内质网应激抑制T细胞功能，这一作用被熊脱氧胆酸所对抗。研究人员展示了，通过改变胆汁酸合成或饮食中熊脱氧胆酸的摄入，可以改善肝癌模型系统中的肿瘤免疫疗法。
附：英文原文
Title: Bile acid synthesis impedes tumor-specific T cell responses during liver cancer
Author: Siva Karthik Varanasi, Dan Chen, Yingluo Liu, Melissa A. Johnson, Cayla M. Miller, Souradipta Ganguly, Kathryn Lande, Michael A. LaPorta, Filipe Araujo Hoffmann, Thomas H. Mann, Marcos G. Teneche, Eduardo Casillas, Kailash C. Mangalhara, Varsha Mathew, Ming Sun, Isaac J. Jensen, Yagmur Farsakoglu, Timothy Chen, Bianca Parisi, Shaunak Deota, Aaron Havas, Jin Lee, H. Kay Chung, Andrea Schietinger, Satchidananda Panda, April E. Williams, Donna L. Farber, Debanjan Dhar, Peter D. Adams, Gen-Sheng Feng, Gerald S. Shadel, Mark S. Sundrud, Susan M. Kaech
Issue&Volume: 2025-01-10
Abstract: The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.
DOI: adl4100
Source: https://www.science.org/doi/10.1126/science.adl4100