title: Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4+T cells that express RORγt and IL-17 (TH17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (Treg) contribute to TH17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to TH17 associated functional plasticity in Treg. In this study, we investigated the phenotype and functional properties of Tregin patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3+Treg, which exclusively occurred within the FOXP3+RORγt+Tregcompartment. The FOXP3+RORγt+Tregretained FOXP3+Tregmarkers and represented an activated subset. The expression of RORγt in Tregmay indicate a phenotypic switch toward TH17 cells. However, the FOXP3+RORγt+Tregproduced both TH17 and TH2 associated pro-inflammatory cytokines, which corresponded with elevated TH17 and TH2 immune responses in PDAC patients. Both the FOXP3+Tregand FOXP3+RORγt+Tregfrom PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3+RORγt+Treghave a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway; Biotechnology Center, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Oslo, Norway.
authors.forename: Stalin
authors.initials: S
authors.lastname: Chellappa
authors.affiliation: Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Hugenschmidt
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway; Biotechnology Center, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Hagness
authors.affiliation: Section for Transplantation Surgery, Oslo University Hospital , Oslo, Norway.
authors.forename: Pål D
authors.initials: PD
authors.lastname: Line
authors.affiliation: Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital , Oslo, Norway.
authors.forename: Knut J
authors.initials: KJ
authors.lastname: Labori
authors.affiliation: Department of Gastrointestinal Surgery, Oslo University Hospital , Oslo, Norway.
authors.forename: Gro
authors.initials: G
authors.lastname: Wiedswang
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway; Biotechnology Center, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy, University of Oslo, Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway; Biotechnology Center, University of Oslo, Oslo, Norway; K.G. Jebsen Inflammation Research Center, University of Oslo, Oslo, Norway; Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.
authors.forename: Einar M
authors.initials: EM
authors.lastname: Aandahl
keywords: FOXP3; RORγt; Th17 cell; Th2 cell; plasticity; regulatory T Cells; suppression; surface Markers