Varanasi Siva Karthik, Chen Dan, Liu Yingluo, Johnson Melissa A, Miller Cayla M, Ganguly Souradipta, Lande Kathryn, LaPorta Michael A, Hoffmann Filipe Araujo, Mann Thomas H, Teneche Marcos G, Casillas Eduardo, Mangalhara Kailash C, Mathew Varsha, Sun Ming, Jensen Isaac J, Farsakoglu Yagmur, Chen Timothy, Parisi Bianca, Deota Shaunak, Havas Aaron, Lee Jin, Chung H Kay, Schietinger Andrea, Panda Satchidananda, Williams April E, Farber Donna L, Dhar Debanjan, Adams Peter D, Feng Gen-Sheng, Shadel Gerald S, Sundrud Mark S, Kaech Susan M
NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA.
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Science. 2025 Jan 10;387(6730):192-201. doi: 10.1126/science.adl4100. Epub 2025 Jan 9.
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 -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.
癌症的代谢格局极大地影响抗肿瘤免疫，但肿瘤微环境中的器官特异性代谢物如何影响免疫监视仍不清楚。我们发现，初级结合胆汁酸和次级胆汁酸（BAs）的积累是人类肝细胞癌和实验性肝癌模型的代谢特征。通过缺失BA结合酶胆汁酸辅酶A：氨基酸酰基转移酶（BAAT）来抑制肝细胞中的结合BA合成，可增强肿瘤特异性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）免疫疗法敏感。此外，不同的BAs对CD8 T细胞的调节作用不同；初级BAs诱导氧化应激，而次级胆汁酸石胆酸通过内质网应激抑制T细胞功能，熊去氧胆酸可对抗这种作用。我们证明，改变BA合成或饮食中熊去氧胆酸的摄入量可改善肝癌模型系统中的肿瘤免疫治疗。
