Bile acid synthesis impedes tumor-specific T cell responses during liver cancer
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 <i>N</i>-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<sup>+</sup> 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.
Authors
- Filipe Araujo Hoffmann
- Peter D. Adams (ORCID: https://orcid.org/0000-0002-0684-1770)
- Aaron Havas (ORCID: https://orcid.org/0000-0003-4291-8015)
- Kathryn Lande (ORCID: https://orcid.org/0009-0005-1613-8981)
- Eduardo Casillas (ORCID: https://orcid.org/0000-0001-9968-565X)
- Kailash Chandra Mangalhara (ORCID: https://orcid.org/0000-0001-7412-3095)
- Cayla M. Miller (ORCID: https://orcid.org/0000-0001-8382-0255)
- Satchidananda Panda (ORCID: https://orcid.org/0000-0002-7855-0091)
- Yagmur Farsakoglu (ORCID: https://orcid.org/0000-0003-2503-906X)
- Gen‐Sheng Feng (ORCID: https://orcid.org/0000-0003-1255-4708)
- S Ganguly (ORCID: https://orcid.org/0000-0002-5149-7315)
- April E. Williams (ORCID: https://orcid.org/0000-0001-9281-8528)
- Dan Chen (ORCID: https://orcid.org/0000-0001-5156-6635)
- H. Kay Chung (ORCID: https://orcid.org/0000-0002-7028-2432)
- Mark S. Sundrud (ORCID: https://orcid.org/0000-0002-4249-0525)
- Marcos G. Teneche (ORCID: https://orcid.org/0000-0003-4785-7987)
- T.-S. Chen
- Thomas H. Mann (ORCID: https://orcid.org/0000-0002-3821-1466)
- Andrea Schietinger (ORCID: https://orcid.org/0000-0003-3644-1687)
- Isaac J. Jensen (ORCID: https://orcid.org/0000-0002-3107-3961)
- Donna L. Färber (ORCID: https://orcid.org/0000-0001-8236-9183)
- Debanjan Dhar (ORCID: https://orcid.org/0000-0001-8739-3684)
- Yingluo Liu (ORCID: https://orcid.org/0009-0009-5704-063X)
- Siva Karthik Varanasi (ORCID: https://orcid.org/0000-0001-5797-2984)
- Gerald S. Shadel (ORCID: https://orcid.org/0000-0003-2899-8717)
- Susan M. Kaech (ORCID: https://orcid.org/0000-0003-1674-1420)
- Melissa Johnson (ORCID: https://orcid.org/0000-0002-6913-6059)
- Shaunak Deota (ORCID: https://orcid.org/0000-0002-4862-7414)
- Ming Sun (ORCID: https://orcid.org/0009-0006-3798-1772)
- Michael A. LaPorta (ORCID: https://orcid.org/0009-0001-0461-5614)
- Jin Lee (ORCID: https://orcid.org/0000-0001-5815-9848)
- Varsha Mathew
- Bianca Parisi (ORCID: https://orcid.org/0000-0001-5273-4354)
Institutions
- Dartmouth College (US)
- Dartmouth Institute for Health Policy and Clinical Practice (US)
- Salk Institute for Biological Studies (US)
- Memorial Sloan Kettering Cancer Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Cornell University (US)
- Discovery Institute (US)
- Columbia University Irving Medical Center (US)
- University of California San Diego (US)
- Parker Institute for Cancer Immunotherapy (US)
- Troy Gastroenterology (US)
- Dartmouth Health (US)
Publication Details
- Journal
- Science
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1126/science.adl4100
- Citations
- 110
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 114.99
Funders
- Cancer Research Institute
- Damon Runyon Cancer Research Foundation
- Vanderbilt University
- Leona M. and Harry B. Helmsley Charitable Trust
- Waitt Foundation
- Dartmouth College
- Dartmouth Cancer Center
- National Institutes of Health
- School of Medicine, Vanderbilt University
- University of California, San Diego
- National Cancer Institute