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.