title: CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice.
abstract: Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer.
authors.affiliation: Authors' Affiliations: Departments of Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Esha
authors.initials: E
authors.lastname: Mathew
authors.forename: Filip
authors.initials: F
authors.lastname: Bednar
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wan
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Collins
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Evans
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Welling
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Marina Pasca
authors.initials: MP
authors.lastname: di Magliano
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D004195:Disease Models, Animal; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D010195:Pancreatitis / Q000150:complications / Q000235:genetics / Q000276:immunology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)