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

Abstract

Abstract. 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 β 1 (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 nonresponders 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.

Oncogenic Kras Activates a Hematopoietic-to-Epithelial IL-17 Signaling Axis in Preinvasive Pancreatic Neoplasia

“…However, functional studies of infiltrating T H 17 cells were not conducted in this study, and their increased recruitment may simply reflect known effects of IL-6. In addition, prior studies have correlated T H 17 cell infiltration and plasma IL-17A levels with poor prognosis in pancreatic cancer patients (He et al, 2011; Vizio et al, 2012). Nevertheless, it is clearly possible that IL-17 signaling may exert opposing influences on pancreatic tumorigenesis at different stages of the disease and in the context of variability in the host immune response.…”

Interleukin-17 Receptor A Signaling in Transformed Enterocytes Promotes Early Colorectal Tumorigenesis

“…The numbers of Th17 cells and expression of IL-17A are increased in human glioma (Hu et al, 2011) and esophageal cancer (Chen et al, 2012). Increased expression of IL-23, IL-17A and TGF-β1 signals adverse prognosis and predicts poor response to chemotherapy in pancreatic carcinoma (Vizio et al, 2012). Th17 cell abundance and IL-17 expression are also elevated in gastric cancer and indicate poor prognosis (Yamada et al, 2012).…”

The correlations between IL-17 vs. Th17 cells and cancer patient survival: a systematic review

“…17,[24][25][26]31 One study showed a correlation between high IL-17 and improved survival in leukemia. 32 Four studies did not observe a significant correlation between high serum IL-17 levels and survival, [33][34][35][36] although one group did find a trend toward poor prognosis (p D 0.05). 36 Overall, a high amount of IL-17 protein in serum has predominantly been correlated with poor survival ( Table 2).…”