Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome

CD4+CD25+FoxP3+ regulatory T cells (Tregs) are understood to maintain peripheral tolerance to self-antigens and inhibit antitumor immune responses. However, compelling evidence suggests that, Tregs provide no anti-inflammatory protection in the tumor microenvironment, but rather contribute to a T helper 17 (Th17)‑driven pro-carcinogenic process. Using three‑color flow cytometry, we evaluated the percentage of circulating CD4+CD25+FoxP3+ Tregs in the peripheral blood of pancreatic carcinoma patients prior to and after chemotherapy [gemcitabine (GEM) alone, or GEM+oxaliplatin (GEMOX) or bevacizumab+capecitabine+radiotherapy (BEV+CAPE+RT)]. Correlations were sought between Treg counts and plasma levels of cytokines relevant to controlling the Treg/Th17 balance, i.e., interleukin (IL)‑23, IL‑17A, IL‑6 and transforming growth factor β1 (TGF‑β1), as measured by ELISA and the clinical features of pancreatic cancer. Treg, IL‑6 and TGF‑β1 levels were higher in locally advanced and metastatic pancreatic carcinoma patients compared to controls. No parameter was correlated with disease stage except IL‑6. IL‑17A and TGF‑β1 were significantly associated with increased risk of poor prognosis. IL‑17A was positively correlated with IL‑23. Treg and IL‑6 levels decreased following GEM monochemotherapy, IL‑17A levels decreased after GEMOX, and IL‑6 levels were reduced subsequent to BEV+CAPE+RT treatment. IL‑23, IL‑17A and TGF‑β1 levels were significantly lower in patients responding to chemotherapy (partial remission/stable disease) than in non-responders to chemotherapy (progressive disease). These results suggest an impact of the Treg/Th17-balance in pancreatic carcinoma, highlighting the significance of TGF‑β1 and IL‑17A as potential prognostic and predictive indicators. Immunological changes induced by mono and/or combined chemotherapy indicate specific windows of opportunity for introducing integrative interventions on a new target in pancreatic cancer, i.e. IL‑17A, possibly improving survival in this highly lethal disease.