Aryl hydrocarbon receptor ligands drive pancreatic cancer initiation and progression through pro-tumorigenic T cell polarization.

Although smoking is a risk factor for pancreatic adenocarcinoma (PDAC), the underlying mechanism promoting tumorigenesis and progression are unknown. Here, we show that aryl hydrocarbon receptor ligands found in cigarette smoke, like the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), promote pancreatic dysplasia and PDAC progression in a mouse model of this disease. This effect is mediated by AhR activation in CD4+ T cells, leading to their polarization to interleukin-22 (IL22) producing TH22 cells and to regulatory T cells (Treg) accumulation, ultimately driving a blunted CD8+ T cell effector response.