Bile Acids Offer New Immunotherapy Targets for Liver Cancer
Researchers at the Salk Institute, led by Professor Ronald Evans, have discovered a meaningful link between bile acids in the liver and the effectiveness of T cells in fighting cancer. Their findings, published recently, suggest manipulating bile acid levels could dramatically improve immunotherapy outcomes for liver cancer patients.
The study began wiht an analysis of human liver cancer biopsies,revealing elevated levels of conjugated bile acids. Subsequent experiments in mice demonstrated that reducing the production of these conjugated bile acids – specifically by removing the BAAT protein responsible for their creation - led to a ample decrease in tumor size. This indicates that modulating BAAT activity could enhance a patient’s response to immunotherapy.
Further inquiry into 20 different bile acids revealed varying effects on T cell function. While most had minimal impact, TCDCA induced harmful oxidative stress.More notably, LCA damaged T cells by causing stress within the endoplasmic reticulum, while UDCA demonstrably improved T cell performance and attracted more immune cells to the liver. Supplementation with UDCA in mice resulted in reduced tumor growth, highlighting its potential as a therapeutic agent.
“By taking this unique approach,we’re able to see that bile acids in the liver are hugely influencing T cells’ ability to do their job and therefore may be a useful therapeutic target,” explained Evans,who is also an assistant professor at the University of Massachusetts Chan Medical School.
The research team believes clinical translation is readily achievable, as UDCA is already used to treat liver disease and could be quickly tested in liver cancer trials.They are also exploring the role of the gut microbiome in regulating bile acid levels, questioning how manipulating gut bacteria could further optimize bile acid balance and impact cancer progression. The team is also investigating whether targeting BAAT could benefit other conditions, including chronic liver disease and obesity.
The study involved a large collaborative effort with researchers from UC San Diego, Sanford Burnham Prebys Medical Discovery Institute, Columbia university, Memorial Sloan Kettering Cancer Center, Weill Cornell Graduate School of Medical Sciences, Parker Institute for Cancer Immunotherapy, and Dartmouth College.
Funding for the research was provided by the National Institutes of Health, Waitt Foundation, Helmsley Charitable Trust, Chapman Foundation, Cancer Research Institute, National Cancer Center, NOMIS Foundation, Salkexcellerators Fellowship, Damon Runyon Fellowship, Audrey Geisel endowed Chair of Biomedical Science, Altman Clinical Translational Research Institute, san Diego Digestive Diseases Research Center, and Dartmouth Cancer center.
