Immunotherapy is a cancer treatment that harnesses the body's own immune defenses to attack tumors. It has shown remarkable success against cancers of the lung, kidney, and bladder but has not worked as well for liver cancer. That gap is troubling because liver cancer cases have nearly tripled over the past four decades.
To explore why liver cancer responds poorly to immunotherapy, scientists at the Salk Institute examined how the immune system interacts with the liver. Using both mouse models and human tumor samples, they discovered that certain bile acids -- molecules produced by the liver to aid digestion -- can interfere with cancer-fighting immune cells known as T cells.
The team pinpointed several bile acids linked to weakened T cell function and faster tumor growth. By blocking the production of these acids, they were able to slow or stop tumor progression. One bile acid, called ursodeoxycholic acid (UDCA), had the opposite effect, enhancing T cell activity in the liver. When researchers increased UDCA levels through dietary supplements, liver tumors in mice shrank. Because UDCA supplements are already approved for other liver diseases, scientists believe they could potentially make immunotherapy more effective for liver cancer patients.
The study, published in Science, sheds light on why immune cells behave differently depending on the tumor's location and identifies new molecular targets to strengthen liver cancer therapies.
"How do organ-specific properties and processes influence the immune response?" asks Professor Susan Kaech, senior author of the study and director of Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis. "Livers have a particularly unique environment, but we didn't really understand how it was affecting the immune and cancer cells. By investigating these liver-specific features, we have identified several potential ways to regulate bile acids, improve T cell performance, and enhance patient outcomes."
The liver generates more than 100 types of bile acids, which travel through the intestines to help digest fats. To combat liver cancer, T cells must function effectively within this chemically rich environment. Past studies have linked high bile acid levels to poor health and cancer progression, but researchers had not previously distinguished the effects of individual bile acids.
"Considering how T cell performance varies across different organs, tissues, and tumors puts us at a great vantage point for looking at ways to optimize cancer treatment," says Siva Karthik Varanasi, former postdoctoral researcher in Kaech's lab and current assistant professor at the University of Massachusetts Chan Medical School. "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."
To better understand these effects, the Salk team first analyzed human liver cancer biopsies to identify which bile acids were present. They found elevated levels of conjugated bile acids and tested whether these compounds contributed to tumor growth. When they removed a protein called BAAT, which produces conjugated bile acids, the tumor load in mice dropped significantly. This suggests that adjusting BAAT activity in humans could improve their response to immunotherapy.
The researchers then examined 20 distinct bile acids to determine how each affected T cells. Most primary bile acids showed little influence, except for one called TCDCA, which triggered oxidative stress -- a harmful molecular imbalance. Secondary bile acids had much stronger effects. One, called LCA, damaged T cell function by causing endoplasmic reticulum stress, while another, UDCA, boosted T cell performance and drew more immune cells to the liver. Increasing UDCA levels through supplementation effectively reduced tumor growth in mice, pointing to a promising strategy for enhancing immunotherapy in liver cancer.
Together, these results suggest that lowering BAAT and increasing UDCA could help control liver tumor growth and strengthen the immune system's response to treatment.
"We're already a huge step ahead when it comes to translating our findings to the clinic, because UDCA supplementation is already used to treat liver disease and could easily be tested in liver cancer next," says Kaech, who also holds the NOMIS Chair at Salk. "We are really excited to also explore the role of the gut microbiome in all of this, since bile acids are a huge part of that picture -- how can we manipulate 'good' and 'bad' bacteria in the microbiome to further regulate bile acid levels? How does the microbiome change during liver cancer? Could probiotics be a therapeutic approach?"
In addition to exploring dietary and microbiome manipulations that could help with liver cancer, the team is curious to see if other conditions could be treated by targeting BAAT. Already, they believe chronic liver disease and obesity may benefit from the same reduction of conjugated bile acids.
Other authors include Dan Chen, Melissa Johnson, Kathryn Lande, Michael LaPorta, Filipe Hoffmann, Thomas Mann, Eduardo Casillas, Kailash Mangalhara, Varsha Mathew, Ming Sun, Yagmur Farsakoglu, Timothy Chen, Bianca Parisi, Shaunak Deota, H. Kay Chung, Satchidananda Panda, April Williams, and Gerald Shadel of Salk; Jin Lee, Yingluo Liu, Cayla Miller, and Gen-Sheng Feng of UC San Diego; Souradipta Ganguly and Debanjan Dhar of UC San Diego and Sanford Burnham Prebys Medical Discovery Institute; Marcos Teneche, Aaron Havas, and Peter Adams of Sanford Burnham Prebys Medical Discovery Institute; Isaac Jensen and Donna Farber of Columbia University; Andrea Schietinger of Memorial Sloan Kettering Cancer Center, Weill Cornell Graduate School of Medical Sciences, and Parker Institute for Cancer Immunotherapy; and Mark Sundrud of Dartmouth College.
The work was supported by the National Institutes of Health (NCI CCSG: P30 014195, S10-OD023689, P30 AG068635, P30 CA014195, P01 AG073084, R01 CA240909-04, R21 AI151562, F31CA278581, CCSG Grant P30CA23100, R01DK137061, R01DK133930, DK120515, R01AI143821, R01AI164772, U01AI163063), 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 (KL2TR001444), San Diego Digestive Diseases Research Center, and Dartmouth Cancer Center.
