Abstract
Abstract A subset of melanoma patients treated with immune checkpoint inhibitors develops vitiligo, a CD8 T cell-mediated autoimmune disease associated with improved patient survival. Using a melanoma-associated vitiligo (MAV) mouse model, CD8 tissue resident memory (TRM) T cells in vitiligo skin were found to be necessary and sufficient for durable tumor immunity. Using immunofluorescence microscopy, we found that skin TRM cells formed large aggregates with CD11c myeloid cells proximal to hair follicles. CD11c depletion resulted in TRM cell loss, revealing an unexpected requirement for continued T cell-dendritic cell (DC) interactions in TRM cell maintenance. We hypothesize that DCs provide instructive signals that are required for continued in situ maturation of CD8 TRM cells. To identify these signals, we disrupted Toll Like Receptor (TLR) signaling in DCs by ablating the MyD88 adapter protein and observed a reduction in skin TRM cell accumulation. This prompted us to explore a role for the microbiota in CD8 TRM formation. Treatment with broad spectrum antibiotics resulted in a 50% reduction in vitiligo incidence. B6 mice from vendors with microbiota differences, exhibited divergent MAV incidence, but upon cohousing or fecal transplantation, mice from both sources exhibited high MAV incidence. Collectively, these findings indicates that the gut-skin microbiota axis plays a critical role in generating tumor protective TRM cells. Future studies seek to identify microbial antigens responsible for promoting TRM differentiation. Supported by T32-AI007363 P30-CA023108
Published Version
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