Abstract 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. Analysis of human pancreata from organ donors revealed that smokers have increased AhR activation relative to non-smokers. Similarly, PDAC tumors from patients with a history of cigarette smoking presented with increased Treg accumulation compared to non-smokers. These findings support a model whereby AhRLs in cigarette smoke promote tumorigenesis and progression of PDAC through dysregulation of immune responses.
Griffith et al. (Thu,) studied this question.