Interleukin-6 Trans-Signaling Pathway Promotes Immunosuppressive Myeloid-Derived Suppressor Cells via Suppression of Suppressor of Cytokine Signaling 3 in Breast Cancer.

Mengmeng Jiang,Jieying Chen,Feng Wei,Rui Zhang,Jinpu Yu,Pengpeng Liu,Yingnan Ye,Wenwen Yu,Wenwen Zhang,Xiubao Ren

doi:10.3389/fimmu.2017.01840

Abstract

Interleukin-6 (IL-6) has been reported to stimulate myeloid-derived suppressor cells (MDSCs) in multiple cancers, but the molecular events involved in this process are not completely understood. We previously found that cancer-derived IL-6 induces T cell suppression of MDSCs in vitro via the activation of STAT3/IDO signaling pathway. In this study, we aimed to elucidate the underlying mechanisms. We found that in primary breast cancer tissues, cancer-derived IL-6 was positively correlated with infiltration of MDSCs in situ, which was accompanied by more aggressive tumor phenotypes and worse clinical outcomes. In vitro IL-6 stimulated the amplification of MDSCs and promoted their T cell suppression ability, which were fully inhibited by an IL-6-specific blocking antibody. Our results demonstrate that IL-6-dependent suppressor of cytokine signaling 3 (SOCS3) suppression in MDSCs induced phosphorylation of the JAK1, JAK2, TYK2, STAT1, and STAT3 proteins, which was correlated with T cell suppression of MDSCs in vitro. Therefore, dysfunction in the SOCS feedback loop promoted long-term activation of the JAK/STAT signaling pathway and predominantly contributed to IL-6-mediated effects on MDSCs. Furthermore, IL-6-induced inhibition of SOCS3 and activation of the JAK/STAT pathway was correlated with an elevated expression of IL-6 receptor α (CD126), in which the soluble CD126-mediated IL-6 trans-signaling pathway significantly regulated IL-6-mediated effects on MDSCs. Finally, IL-6-induced SOCS3 dysfunction and sustained activation of the JAK/STAT signaling pathway promoted the amplification and immunosuppressive function of breast cancer MDSCs in vitro and in vivo, and thus blocking the IL-6 signaling pathway is a promising therapeutic strategy for eliminating and inhibiting MDSCs to improve prognosis.

Highlights

Increasing evidence has highlighted the importance of crosstalk between cancer cells and the surrounding microenvironment in the initiation and progression of various cancers [1,2,3]
According to the number of CD33+ myeloid-derived suppressor cells (MDSCs) that infiltrated locally, breast cancer patients were divided into lowly infiltrated MDSC group (MDSCslow) and highly infiltrated MDSC group (MDSCshigh)
Similar trends were observed in MDSChigh patients as compared with MDSClow patients, where more infiltrated MDSCs were detected in cancer tissues at more advanced pathological stages, with higher histological grade, more lymph node metastasis, and larger tumor size (P < 0.001, P < 0.001, P = 0.025, P = 0.018; P < 0.001, P = 0.007; P = 0.022, P = 0.032, respectively, Table 4). These results demonstrated that breast cancers with higher IL-6 expression and greater MDSC infiltration possess a higher potential for invasion and metastasis

Summary

Introduction

Increasing evidence has highlighted the importance of crosstalk between cancer cells and the surrounding microenvironment in the initiation and progression of various cancers [1,2,3]. The tumor microenvironment is composed of multiple immunosuppressive cells, among which myeloid-derived suppressor cells (MDSCs) play a vital role in promoting tumor invasion and metastasis [3]. Myeloid-derived suppressor cells are a heterogeneous population of immature myeloid cells with suppressive effects on both innate and adaptive immunity; they are regarded as a major obstacle in antitumor immunotherapy [4]. Different MDSCs subsets display varied phenotypes in mice or in humans. Early-stage MDSCs (eMDSCs), which comprised more immature progenitors than M-MDSCs and PMN-MDSCs, are defined as specific MDSCs subset expressing Lin−HLA-DR−CD33+ in human tumors [5]. We identified a subset of poorly differentiated eMDSCs in breast cancer that expressed an immature phenotype of Lin−HLA-DR−CD45+CD33+CD13+CD14−CD15− and displayed potent suppression of T cells in vitro and in vivo [6]. We found that cancer-derived interleukin-6 (IL-6) induces the immunosuppressive ability of MDSCs by activating the STAT3/IDO signaling pathway, but the detailed molecular events are unclear [7]

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