T cell adaption to bile acids is critical for their responses during liver tumors.

Introduction/Rationale: CD8+ T cells have an incredible capacity to infiltrate almost every tissue in the body. Yet, it is not known how T cells adapt to different tissue microenvironments. This is particularly important during diseases such as cancer, as CD8+ T cells are often found to be in a state of dysfunction. Therefore, we presume that failure to adapt to the local microenvironment contributes to T cell dysfunction within tumors.

Methods: To determine how T cell adaptation influences their function, we used the liver and liver derived cancer as model system, as liver tumors showed elevated taurine-conjugated bile acids which are primarily synthesized by the liver. Using hepatocyte-targeting AAVs to knock out liver genes, we identified the role of bile acid synthesis enzymes in shaping T cell responses.

Results: We found that in liver tumors, tumor-reactive T cells took up elevated levels of conjugated bile acids than the non-tumor-reactive T cells. This uptake of bile acids was associated with lower expression of bile acid efflux transporters - Abcb1a/b and Slco3a1. Knockdown of either of these bile acid efflux transporters in T cells led to bile-acid-mediated mitochondrial toxicity and cell death. Whereas, overexpressing SLCO3A1 was sufficient to promote survival of T cells in bile-acid-rich liver tumors. More importantly, knocking down enzymes in the bile acid synthesis pathway led to the identification of the bile acid–conjugating enzyme BAAT as a negative regulator of T cell responses to the tumor. Thus, BAAT knockout liver tumors displayed lower conjugated bile acids associated with elevated tumor-reactive T cell responses, indicating its therapeutic potential. We are now determining the role of different bile acid receptors in T cell differentiation.

Conclusion: In conclusion, we found that bile acids in the liver act as tissue-specific regulators of T cell responses, and T cell adaptation to such bile acids is essential for survival and responsiveness, especially when the tumor arises in the liver.