Bile acid synthesis impedes tumor-specific T cell responses during liver cancer

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Salk Institute; University of California System; University of California San Diego; Sanford Burnham Prebys Medical Discovery Institute; University of California System; University of California San Diego; Salk Institute; Columbia University; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Salk Institute; Memorial Sloan Kettering Cancer Center; Cornell University; Dartmouth College; Dartmouth College; University of Massachusetts System; University of Massachusetts Worcester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9548
• DOI: 10.1126/science.adl4100
• 发表日期: 2025-01-10
• 页码: 192-201
• 关键词: hepatocellular-carcinoma; ursodeoxycholic acid; receptor; atezolizumab; bevacizumab; cholestasis; dysfunction; expression; therapy; antigen

摘要

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.