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 |
