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 (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.