MicroRNA-200c Promotes Suppressive Potential of Myeloid-Derived Suppressor Cells by Modulating PTEN and FOG2 Expression.

Shiyue Mei,Yu Liu,Yugang Huang,Jiaxuan Xin,Xiaomin Su,Xue Liang,Yuan Zhang,Hui Yan,Rongcun Yang,Jun Li

doi:10.1371/journal.pone.0135867

Abstract

Myeloid-derived suppressor cells (MDSCs) constitute one of the major populations that potently suppress anti-tumor immune responses and favor tumor growth in tumor microenvironment. However, the mechanism(s) regulating the differentiation and suppressive function of tumor-associated MDSCs remain(s) unclear. Here, we identified a microRNA-200c (miR-200c), whose expression was dramatically induced by tumor-derived factors. Meanwhile, we also demonstrated that GM-CSF was a main inducer of miR-200c in tumor environment, and miR-200c in turn promoted the expansion and immune suppressive activity of MDSCs via targeting phosphatase and tensin homolog (PTEN) and friend of Gata 2 (FOG2), which can lead to STAT3 and PI3K/Akt activation. Finally, we examined in vivo suppressive function of miR-200c transfected MDSCs and found that miR-200c could remarkably promote tumor growth via modifying MDSCs. Thus, GM-CSF induced miR-200c in tumor environment plays a critical role in governing the expansion and functions of tumor-associated MDSCs and serves as a potential target in immunotherapy against tumor.

Highlights

Myeloid derived suppressor cells (MDSCs) accumulate in large numbers in tumor microenvironment and represent a key player mediating tumor immune tolerance [1,2,3]
We selected microRNA-200c as the focus microRNA of this study with the potential to regulate the differentiation and function of myeloid-derived suppressor cells (MDSCs) in tumor microenvironment because of the facts that miR-200c could be detected in myeloid derived CD11b+Gr-1+ cells cells [26]
Tumor-associated factors contributed to miR-200c upregulation, suggesting that miR-200c may be involved in the differentiation and suppressive function of tumor associated MDSCs

Summary

Introduction

Myeloid derived suppressor cells (MDSCs) accumulate in large numbers in tumor microenvironment and represent a key player mediating tumor immune tolerance [1,2,3]. MDSCs are characterized by the simultaneously expression of the myeloid markers Gr-1 and CD11b [4], which are further subdivided into two subsets including mononuclear cells (MO-MDSCs) with a phenotype of inflammatory monocytes, expressing Ly6C marker (CD11b+Ly6G-Ly6Chigh) and polymorphonuclear cells (PMN-MDSCs) with a phenotype of immature neutrophils, expressing Ly6G marker (CD11b+Ly6G+Ly6Clow) [3, 5]. The phenotype of MDSCs are less well defined, but are generally regarded as CD11b+CD14-CD33+ cells or Lin-HLA-DR-CD33+ cells [6]. Two main subpopulations of MDSCs in patients have been recently identified as CD14+ monocytes and CD15+ neutrophils MDSCs [7]. PLOS ONE | DOI:10.1371/journal.pone.0135867 August 18, 2015

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Conclusion