2025/09/04 by Brian D. Griffith, Padma Kadiyala, Jake McGue +18 · 1 voice
Biochemistry, Genetics and Molecular Biology · Environmental Science · Medicine · #Carcinogens and Genotoxicity Assessment #Smoking Behavior and Cessation #Toxic Organic Pollutants Impact
paper · pdf · doi:10.1158/2159-8290.cd-25-0377
openalex publication_date 2025/09/04 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/27
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. SIGNIFICANCE: Our study investigates the mechanistic link between AHRL and pancreatic cancer. We determined that AHRLs polarize naïve T cells, resulting in increased production of IL22 and immunosuppression. Our findings identify a novel signaling axis linking environmental chemicals to pancreatic tumorigenesis via the immune system. See related commentary by Zhao and Hill, p. 13.