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

Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4T cells that express RORγt and IL-17 (T17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T) contribute to T17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T17 associated functional plasticity in T. In this study, we investigated the phenotype and functional properties of T in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3T, which exclusively occurred within the FOXP3RORγtT compartment. The FOXP3RORγtT retained FOXP3T markers and represented an activated subset. The expression of RORγt in T may indicate a phenotypic switch toward T17 cells. However, the FOXP3RORγtT produced both T17 and T2 associated pro-inflammatory cytokines, which corresponded with elevated T17 and T2 immune responses in PDAC patients. Both the FOXP3T and FOXP3RORγtT from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3RORγtT have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.