Title |
Interleukin-6 Trans-Signaling Pathway Promotes Immunosuppressive Myeloid-Derived Suppressor Cells via Suppression of Suppressor of Cytokine Signaling 3 in Breast Cancer
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Published in |
Frontiers in immunology, December 2017
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DOI | 10.3389/fimmu.2017.01840 |
Pubmed ID | |
Authors |
Mengmeng Jiang, Jieying Chen, Wenwen Zhang, Rui Zhang, Yingnan Ye, Pengpeng Liu, Wenwen Yu, Feng Wei, Xiubao Ren, Jinpu Yu |
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. |
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Country | Count | As % |
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Unknown | 77 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 11 | 14% |
Student > Bachelor | 9 | 12% |
Student > Master | 8 | 10% |
Student > Doctoral Student | 6 | 8% |
Researcher | 5 | 6% |
Other | 9 | 12% |
Unknown | 29 | 38% |
Readers by discipline | Count | As % |
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Agricultural and Biological Sciences | 8 | 10% |
Medicine and Dentistry | 4 | 5% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 1% |
Other | 2 | 3% |
Unknown | 32 | 42% |