Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer

Stalin Chellappa; Harald Hugenschmidt; Morten Hagness; Pål D Line; Knut J Labori; Gro Wiedswang; Kjetil Taskén; Einar M Aandahl

doi:10.1080/2162402X.2015.1102828

Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer

Oncoimmunology. 2015 Oct 29;5(4):e1102828. doi: 10.1080/2162402X.2015.1102828. eCollection 2016 Apr.

Authors

Stalin Chellappa¹, Harald Hugenschmidt², Morten Hagness³, Pål D Line⁴, Knut J Labori⁵, Gro Wiedswang⁶, Kjetil Taskén⁷, Einar M Aandahl³

Affiliations

¹ 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.
² Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway.
³ 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.
⁴ Section for Transplantation Surgery, Oslo University Hospital , Oslo, Norway.
⁵ Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital , Oslo, Norway.
⁶ Department of Gastrointestinal Surgery, Oslo University Hospital , Oslo, Norway.
⁷ 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.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4⁺T cells that express RORγt and IL-17 (T_H17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T_reg) contribute to T_H17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T_H17 associated functional plasticity in T_reg. In this study, we investigated the phenotype and functional properties of T_reg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3⁺T_reg, which exclusively occurred within the FOXP3⁺RORγt⁺T_reg compartment. The FOXP3⁺RORγt⁺T_reg retained FOXP3⁺T_reg markers and represented an activated subset. The expression of RORγt in T_reg may indicate a phenotypic switch toward T_H17 cells. However, the FOXP3⁺RORγt⁺T_reg produced both T_H17 and T_H2 associated pro-inflammatory cytokines, which corresponded with elevated T_H17 and T_H2 immune responses in PDAC patients. Both the FOXP3⁺T_reg and FOXP3⁺RORγt⁺T_reg from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3⁺RORγt⁺T_reg have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.

Keywords: FOXP3; RORγt; Th17 cell; Th2 cell; plasticity; regulatory T Cells; suppression; surface Markers.

Publication types

Research Support, Non-U.S. Gov't