Investigating AhR as a mechanism of CD8+ T cell modulation by microbial-derived metabolites in PDAC 2802

Description Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year-survival of common solid cancer types and responds poorly to immunotherapy despite an abundant intra-tumour immune infiltrate. The microbiota has been reported to impact tumour characteristics and survival, at least partially by limiting CD8+ T cell function. The microbiota can potentially influence immune function through metabolites, including indole production as a result of microbial tryptophan metabolization. The aryl hydrocarbon receptor (AhR) is a key cellular response pathway in the host-microbiota axis that may play an immunosuppressive role in CD8+ T cells. Since AhR can be activated by microbial-derived indoles, we tested the hypothesis that microbiota-produced indoles suppress intratumoural CD8+ T cell function via AhR activation, thus promoting disease progression. Using an orthotopic model of PDAC, we found that tumour burden was reduced in CD8-specific AhR knockout mice compared to the littermate controls. Further, murine PDAC tumours have a greater concentration of indole compounds compared to healthy pancreases. Moreover, exposure to these indole compounds activated AhR in CD8+ T cells, significantly suppressing their acquisition of an inflammatory phenotype. In summary, our data suggest that microbial-derived metabolites can suppress CD8+ T cell function in PDAC through activation of AhR Funding Sources NIH, CIHR, and TFRI Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)