Interleukin-6 Trans-Signaling Pathway Promotes Immunosuppressive Myeloid-Derived Suppressor Cells via Suppression of Suppressor of Cytokine Signaling 3 in Breast Cancer.
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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Interleukin-6 反式信号通路通过抑制乳腺癌中细胞因子信号传导 3 的抑制子来促进免疫抑制性骨髓源性抑制细胞
DOI：
10.3389/fimmu.2017.01840
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发表时间：
2017
影响因子：
7.3
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Jiang M;Chen J;Zhang W;Zhang R;Ye Y;Liu P;Yu W;Wei F;Ren X;Yu J
白细胞介素-6（IL-6）已被报道在多种癌症中刺激骨髓源性抑制细胞（MDSC），但参与此过程的分子事件尚未完全了解。我们先前发现，癌源性IL-6通过激活STAT 3/IDO信号通路在体外诱导MDSC的T细胞抑制。在这项研究中，我们的目的是阐明潜在的机制。我们发现，在原发性乳腺癌组织中，癌源性IL-6与原位MDSC浸润呈正相关，这伴随着更具侵袭性的肿瘤表型和更差的临床结局。在体外IL-6刺激MDSC的扩增，并促进其T细胞抑制能力，这是完全抑制的IL-6特异性阻断抗体。我们的研究结果表明，MDSC中的IL-6依赖性细胞因子信号转导抑制因子3（SOCS 3）抑制诱导JAK 1，JAK 2，TYK 2，STAT 1和STAT 3蛋白的磷酸化，这与体外MDSC的T细胞抑制相关。因此，SOCS反馈环的功能障碍促进JAK/STAT信号通路的长期激活，并主要促成IL-6介导的对MDSC的作用。此外，IL-6诱导的SOCS 3抑制和JAK/STAT通路的激活与IL-6受体α（CD 126）的表达升高相关，其中可溶性CD 126介导的IL-6反式信号通路显著调节IL-6介导的对MDSC的作用。最后，IL-6诱导的SOCS 3功能障碍和JAK/STAT信号通路的持续激活促进了乳腺癌MDSC在体外和体内的扩增和免疫抑制功能，因此阻断IL-6信号通路是消除和抑制MDSC以改善预后的有希望的治疗策略。
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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影响因子：
--
作者：
Chen MF;Kuan FC;Yen TC;Lu MS;Lin PY;Chung YH;Chen WC;Lee KD
通讯作者：
Lee KD
影响因子：
32.4
作者：
Babon JJ;Kershaw NJ;Murphy JM;Varghese LN;Laktyushin A;Young SN;Lucet IS;Norton RS;Nicola NA
通讯作者：
Nicola NA
影响因子：
29.4
作者：
Isomoto, Hajime;Mott, Justin L.;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
9.7
作者：
Hiwatashi, Kiyokazu;Tamiya, Taiga;Yoshimura, Akihiko
通讯作者：
Yoshimura, Akihiko
影响因子：
7.2
作者：
Gunaydin, Gurcan;Kesikli, S. Altug;Guc, Dicle
通讯作者：
Guc, Dicle