Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13

Abstract

We undertook a comprehensive analysis of circulating myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) in pancreatic, esophageal and gastric cancer patients and investigated whether MDSCs are an independent prognostic factor for survival. We evaluated a series of plasma cytokines and in particular re-evaluated the Th2 cytokine interleukin-13 (IL-13). Peripheral blood was collected from 131 cancer patients (46 pancreatic, 60 esophageal and 25 gastric) and 54 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR− Lin1low/− CD33+ CD11b+) and Treg (CD4+ CD25+ CD127low/− FoxP3+) percentages. Plasma IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, IFN-γ, TNF-α and VEGF levels were analyzed by the Bio-Plex cytokine assay. Plasma arginase I levels were analyzed by ELISA. MDSCs and Tregs were statistically significantly elevated in pancreatic, esophageal and gastric cancer compared with controls, and MDSC numbers correlated with Treg levels. Increasing MDSC percentage was associated with increased risk of death, and in a multivariate analysis, MDSC level was an independent prognostic factor for survival. A unit increase in MDSC percentage was associated with a 22% increased risk of death (hazard ratio 1.22, 95% confidence interval 1.06–1.41). Arginase I levels were also statistically significantly elevated in upper gastrointestinal cancer patients compared with controls. There was Th2 skewing for cytokine production in all three diseases, and importantly there were significant elevations of the pivotal Th2 cytokine interleukin-13, an increase that correlated with MDSC levels.

Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype

“…We found that plaGR-MDSCs led to a polarization of CD4 + T cells toward a Th2 phenotype. This is in line with studies in mice and humans showing an association between MDSC count and Th2 cytokine expression (15,(57)(58)(59). The present study, however, is to our knowledge the first to show a direct impact of MDSCs on T cell polarization in humans.…”

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

“…The importance of CD4 + IL-4 + cells in malignancy was recently demonstrated in a mouse mammary carcinoma model, in which production of IL-4 by helper T cells was able to polarize macrophages, resulting in increased lung metastasis [6]. Similarly, increased plasma levels of IL-13 in patients with pancreatic, gastric and esophageal cancers was positively correlated to increased numbers of myeloid derived suppressor cells [51]. Both these studies showed important downstream effects of the shift to a type 2 response, but did not examine the preliminary cause of the shift.…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…Furthermore, IL-1β has been found to up-regulate TNF-α concentrations in the tumor microenvironment through induction of the production of latter cytokine by myeloid and/or tumor cells [71,72]. In addition, IL-1β has been shown to stimulate the production of IL-10, IL-5 and IL-13, which induced type 2 immune reactions and attracted MDSCs to the tumor site [73,74]. Finally, it has been recently reported that IL-1β could induce and maintain tumor angiogenesis by stimulating the VEGF production [66,75].…”