MAIT cell: microbiome crosstalk in antitumor immunity - PROJECT SUMMARY The composition of microorganisms that inhabit the gut, known as the gut microbiome, has been strongly associated with the pathogenesis of several diseases including cancer, diabetes, and multiple sclerosis. Notably, several high-profile studies have reported that the composition of the gut microbiome is correlated with responses to immune checkpoint inhibitors (ICIs) in human cancer patients. While these studies have proposed several mechanisms accounting for this phenomenon, a specific set of cellular and molecular interactions that explains these responses remains to be elucidated. One possible mechanism is through the immunologic recognition of the byproducts of microbial metabolism. Mucosal-associated invariant T (MAIT) cells are an abundant, highly conserved subset of innate-like T cells that recognize products of microbial riboflavin synthesis presented by the non-polymorphic HLA-like molecule, MR1. Mice grown in germfree conditions have a significant reduction in MAIT cells and the introduction of bacteria with high production of riboflavin drastically increases MAIT cell frequency and activation. Our preliminary data indicate that MAIT cells are found in human melanoma tumors. Furthermore, we found that patients with stage III/IV melanoma have significantly decreased frequencies of MAIT cells amongst their PBMCs, which can be reversed upon anti-PD-1 immunotherapy treatment in responsive patients but not in non-responsive patients. Most strikingly, we observed that patients with high frequencies of circulating MAIT cells had significantly improved overall survival compared to those with low frequencies. Furthermore, we have found that the tumors of responding patients have increased expression of MR1 mRNA compared to non-responders. Interestingly, responsive patients also show increased relative abundance of riboflavin-synthesizing bacteria in their gut microbiome compared to non-responders. Additionally, in our novel MAIT cell deficient mouse model, syngeneic melanoma tumors grow significantly faster and antitumor immunity is significantly diminished compared to wild type mice. Key questions arise from these observations. First, how are riboflavin biosynthesis and MAIT cell functions influenced by ICI treatment? Additionally, what role do MAIT cells play in tumor immunity and what therapeutic benefit can MAIT cell-directed therapies offer when combined with ICI treatment? We hypothesize that MAIT cells are required for anti- melanoma immunity and that activated MAIT cells link the microbiome and tumor immunity through microbial riboflavin synthesis. This hypothesis will be addressed in the following Specific Aims: (1) Determine the mechanism underlying the association between MAIT cells and the dynamics of riboflavin-synthesizing microbes in the gut microbiome during immune checkpoint inhibitor therapy; and (2) Define the contributions of MAIT cells to ICI therapy responses. Should this study reveal a role for MAIT cells in anti-tumor immunity that is dependent the microbiome, modalities aimed at expanding and/or activating MAIT cells during therapy may provide substantial clinical benefit for melanoma patients.
