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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Our study investigates the mechanistic link between AHRL and pancreatic cancer. We determined that AHRLs polarize na\u00efve 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.<\/jats:p>\n                    <jats:p>See related commentary by Zhao and Hill, p. 13<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0377","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T14:02:12Z","timestamp":1756994532000},"page":"114-134","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Aryl Hydrocarbon Receptor Ligands Drive Pancreatic Cancer Initiation and Progression through Protumorigenic T-cell Polarization"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6580-7217","authenticated-orcid":false,"given":"Brian D.","family":"Griffith","sequence":"first","affiliation":[{"name":"1Department of Surgery, University of Michigan, Ann Arbor, 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