Aryl Hydrocarbon Receptor Ligands Drive Pancreatic Cancer Initiation and Progression through Protumorigenic T-cell Polarization
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons de résection d'adénocarcinomes du pancréas d'origine humaine, cette étude identifie le mécanisme par lequel les ligands du récepteur d'aryl hydrocarbone, présents dans la fumée de cigarette (exemple : la 2,3,7,8-tétrachlorodibenzo-p-dioxine), favorisent la tumorigenèse et la progression tumorale via la polarisation des lymphocytes T
Although smoking is a risk factor for pancreatic adenocarcinoma (PDAC), the underlying mechanisms promoting tumorigenesis and progression are unknown. In this study, we show that aryl hydrocarbon receptor (AHR) ligands found in cigarette smoke, like the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, 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 IL22-producing TH22 cells and regulatory T cell 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 nonsmokers. Similarly, PDAC tumors from patients with a history of cigarette smoking presented with increased regulatory T-cell accumulation compared with nonsmokers. These findings support a model whereby AHR ligands (AHRL) in cigarette smoke promote tumorigenesis and progression of PDAC through dysregulation of immune responses.
Cancer Discovery , article en libre accès, 2025