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

Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4(+)T cells that express RORt and IL-17 (T(H)17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T-reg) contribute to T(H)17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T(H)17 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(+)RORt(+)T(reg) compartment. The FOXP3(+)RORt(+)T(reg) retained FOXP3(+)T(reg) markers and represented an activated subset. The expression of RORt in T-reg may indicate a phenotypic switch toward T(H)17 cells. However, the FOXP3(+)RORt(+)T(reg) produced both T(H)17 and T(H)2 associated pro-inflammatory cytokines, which corresponded with elevated T(H)17 and T(H)2 immune responses in PDAC patients. Both the FOXP3(+)T(reg) and FOXP3(+)RORt(+)T(reg) from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3(+)RORt(+)T(reg) have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.