Abstract
Infectious agents are estimated to cause approximately 18% of cancers worldwide, supporting a link between microbial products and carcinogenesis. The diverse array of commensal microorganisms that reside at barrier sites of the human body, collectively termed the microbiome, provide the primary source of constitutive microbial stimulation and promote immune homeostasis through their release of microbial products, including derivatives of vitamin synthesis. Mucosal-associated invariant T (MAIT) cells are unconventional T-cells that recognize microbial-derived metabolites and provide an initial defense to pathogens through their rapid production of type-1 or type-17 cytokines. While MAIT-cells have been shown to infiltrate colorectal tumors, it remains to be determined how MAIT-cells contribute to tumorigenesis and whether commensals regulate MAIT-cell function. Here we show that MAIT-cells are a substantial skin-resident population capable of producing IL-17A. IL-23 signaling promotes the accumulation of cutaneous MAIT-cells and skin commensals induce local MAIT-cell proliferation and IL-1-dependent IL-17A production. In the absence of commensals, MAIT-cells are dramatically decreased, indicating that the microbiota is necessary for the development of this population. Utilizing MAIT-cell-deficient mice, we demonstrate that cutaneous MAIT-cells promote wound healing and inhibit the colonization of pathogens. This work identifies MAIT-cells as the only cell population that is entirely dependent on the microbiota and reveals the mechanism by which these cells respond to the commensal microbial community. Since IL-17A promotes tumor vascularization and neutrophil recruitment, the high frequency of MAIT-cells in human skin suggests that modulation of the skin-resident bacteria may have clinical applications for the progression of melanoma, and current studies are exploring this possibility using the B16 melanoma model in mice.This work was supported by the NIH Intramural Research Program. MGC is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute.
Citation Format: Michael G. Constantinides, Samira Tamoutounour, Jonathan L. Linehan, Shurjo Sen, Jahangheer Shaik, Sobhan Roy, Erin J. Adams, Yasmine Belkaid. Mucosal-associated invariant T-cells respond to the cutaneous microbiota and promote skin immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR16.
