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 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.

Regulatory T‐cell heterogeneity and the cancer immune response

“…32 RORγt + FOXP3 + Tregs were also upregulated in the blood from people with pancreatic cancer, compared to age-matched healthy controls. 33 RORγt + FOXP3 + Tregs in CRC and pancreatic patients produced both IL-10 and IL-17. 32,33 These data indicate that perturbations in these populations in cancer may influence disease and potentially contribute to poor outcomes for patients.…”

“…RORγt + FOXP3 + Tregs have been identified in CRC patients and were enriched in patients with late‐stage cancer 32 . RORγt + FOXP3 + Tregs were also upregulated in the blood from people with pancreatic cancer, compared to age‐matched healthy controls 33 . RORγt + FOXP3 + Tregs in CRC and pancreatic patients produced both IL‐10 and IL‐17 32 , 33 .…”

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy

“…IL-17, IL-6) and Th2 ( e.g. IL-4, IL-13, IL-33) responses – effectively suppressing anti-tumor T cell activity while promoting chronic inflammation [60]. This finding correlates with resected human PDA specimens demonstrating expanded intra-tumoral Tregs and Th17 cells [17].…”

“…There is debate and ongoing research regarding the most important features of Tregs and their interactions that help to enable tumor evasion of immune eradication; however expansion of Tregs in peripheral blood and tumor tissue has been shown to correlate with poor prognosis [56–58]. Th1 (T-bet + ), Th2 (GATA-3 + ), and Th17 (ROR-gamma-t + ) have recently been shown to be not only T helper subtypes, but also dynamic phenotypes of Treg cells [59, 60]. GATA3 expression has been shown to be critical to Treg functions during inflammation, and PDA is associated with chronic inflammation [61, 62].…”

T lymphocyte subsets in cancer immunity: Friends or foes

“…In several studies, it has been documented that RORγt + FOXP3 + Treg cells enriched colorectal and pancreatic cancers, and are, therefore, found in higher numbers compared to control tissues. As a matter of fact, these regulatory cells produced both IL‐10 and IL‐17 within the TME, and are likely linked to poor outcomes in cancer patients . Whereas the exhaustion process was well documented for effector T cells, explaining how these cells could lose their effector functions within the tumor site, it is not clear whether and how this process occurs in Treg cells.…”