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


Authors: Varanasi, S. K.; Chen, D.; Liu, Y.; Johnson, M. A.; Miller, C. M.; Ganguly, S.; Lande, K.; LaPorta, M. A.; Hoffmann, F. A.; Mann, T. H.; Teneche, M. G.; Casillas, E.; Mangalhara, K. C.; Mathew, V.; Sun, M.; Jensen, I. J.; Farsakoglu, Y.; Chen, T.; Parisi, B.; Deota, S.; Havas, A.; Lee, J.; Chung, H. K.; Schietinger, A.; Panda, S.; Williams, A. E.; Farber, D. L.; Dhar, D.; Adams, P. D.; Feng, G. S.; Shadel, G. S.; Sundrud, M. S.; Kaech, S. M.
Article Title: Bile acid synthesis impedes tumor-specific T cell responses during liver cancer
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.
Keywords: liver cell carcinoma; carcinoma, hepatocellular; liver neoplasms; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; metabolism; animals; mice; hepatocytes; cell line, tumor; biosynthesis; immunology; immunotherapy; liver tumor; tumor cell line; oxidative stress; liver cell; drug therapy; acyltransferase; programmed death 1 receptor; tumor microenvironment; ursodeoxycholic acid; acyltransferases; endoplasmic reticulum stress; bile acid; immune checkpoint inhibitor; humans; human; bile acids and salts; programmed cell death 1 receptor; immune checkpoint inhibitors; lithocholic acid
Journal Title: Science
Volume: 387
Issue: 6730
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2025-01-10
Start Page: 192
End Page: 201
Language: English
DOI: 10.1126/science.adl4100
PUBMED: 39787217
PROVIDER: scopus
PMCID: PMC12166762
DOI/URL:
Notes: Article -- Source: Scopus
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