Exercise-induced microbial vitamin B9 metabolite drives CD8 T cell antitumor immunity and enhances ICI efficacy in preclinical melanoma 2988

Abstract Description A sedentary lifestyle significantly increases the risk of cancer. In contrast, exercise has been associated with enhanced antitumor immunity and improved immune checkpoint inhibitor (ICI) efficacy in cancers like melanoma. However, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we show for the first time that exercise-induced changes to the microbiota are a key mechanism by which exercise promotes antitumor immunity via a previously undefined mechanism. First, we show exercise-mediated tumor restraint relies on adaptive immunity, specifically CD8 T cells, and an intact microbiota. We then show that the functionally and compositionally distinct exercised microbiota is sufficient to confer tumor suppression. Through untargeted metabolomics, we show that exercise promotes microbial vitamin B9 metabolism, leading to enrichment of microbial metabolite formate. We demonstrate that formate directly enhances Tc1 function in vitro and promotes tumor antigen-specific Tc1 immunity and improved ICI efficacy in vivo. We found that transcription factor Nuclear Factor Erythroid 2-related factor 2 (Nrf2) is required for formate-mediated enhancement of Tc1 function in vitro and the exercise-mediated antitumor effect in vivo. Through this study, we unveil a previously unrecognized mechanism in which exercise, by modulating the production of a microbiota metabolite, promotes antitumor immunity and ICI efficacy in melanoma. Funding Sources Supported by: NCI R21-CA259636, NCI P30-CA047904, NCI T32-CA082084, Melanoma Research Alliance (MRA)-820677, NIDDK R01-DK130897, and UPMC Hillman Cancer Center SPORE Melanoma NIH P50-CA254865. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)