Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer

Abstract

Pancreatic cancer (PC) mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells (CSCs) are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells (Mo-MDSC) on ALDH1Bright CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC (CD11b+/Gr1+/Ly6G−/Ly6Chi) significantly increase the frequency of ALDH1Bright CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14+ peripheral blood monocytes into Mo-MDSC (CD14+/HLA-DRlow/−) in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1Bright CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1Bright CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1Bright CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-014-1527-x) contains supplementary material, which is available to authorized users.

STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells

“…In Tregs, STAT3 functionally and physically interacts with FOXP3 (14), which might explain why STAT3 enhances the function of FOXP3 þ Tregs (15). STAT3 can be activated in distinct myeloid cell types, including tumor-associated macrophages and myeloidderived suppress cells, stimulating their immunosuppressive function (16,17). In dendritic cells, depletion of STAT3 improves their capacity to present tumor antigens and to stimulate protective anticancer immune responses (18).…”

miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma

“…The role of STAT3 in the expression of the onco-mir miR-21 is particularly important because constitutive activation of STAT3 has been demonstrated in a large number of diverse human tumors, and considerable evidence suggests that constitutive STAT3 activation actively participates in tumor formation and progression. 24,25 Abnormal STAT3 protein activation has been identified in many cancers of the breast, 26 prostate, 27 and pancreas, 28 as well as cancers of blood-forming cells (leukemia and lymphoma). 29,30 Normally, the STAT3 protein is switched on and off in response to signals that control cell growth and development.…”

MDSCs in cancer: Conceiving new prognostic and therapeutic targets

“…Interference with MDSC tumor trafficking increased tumor cell senescence induced by chemotherapy in PTEN −/− mice. Accordingly, in a preclinical model of pancreatic cancer, MO-MDSCs triggered proliferation of aldehyde dehydrogenase-1 + (ALDH1) pancreatic cancer stem cells (CSCs) and a similar effect was observed in pancreatic adenocarcinoma (PDAC) patients, where human CD14 + HLA-DR − MDSCs helped the proliferation of ALDH1 + CSCs and induced mesenchymal features on tumor cells [130]. Lower amounts of MDSCs were recruited in tumors of G-CSFR deficient mice and this correlated with decreased frequency of ALDH1 + CSCs.…”