SOCS3 Deficiency in Myeloid Cells Promotes Tumor Development: Involvement of STAT3 Activation and Myeloid-Derived Suppressor Cells.
SOCS3 Deficiency in Myeloid Cells Promotes Tumor Development: Involvement of STAT3 Activation and Myeloid-Derived Suppressor Cells.
复制标题
DOI：
10.1158/2326-6066.cir-15-0004
复制
发表时间：
2015-07
影响因子：
10.1
通讯作者：
Qin H
中科院分区：
文献类型：
--
作者：
Yu H;Liu Y;McFarland BC;Deshane JS;Hurst DR;Ponnazhagan S;Benveniste EN;Qin H
细胞因子信号转导抑制因子（SOCS）蛋白是JAK/STAT通路的负调节因子，并且通常作为肿瘤抑制因子起作用。SOCS 3的缺乏特别导致STAT 3转录因子的活化增强，其具有促进肿瘤存活同时抑制抗肿瘤免疫的惊人能力。我们首次报道了骨髓细胞中SOCS 3的基因缺失显著增强了肿瘤生长，这与肿瘤微环境中骨髓源性抑制细胞（MDSC）水平升高以及肿瘤中CD 8 + T细胞浸润减少相关。MDSC在促进肿瘤生长中的重要性通过MDSC耗尽后肿瘤生长减少来证明。此外，SOCS 3缺陷型骨髓来源的细胞表现出增强的STAT 3活化，并优先分化为Gr-1+ CD 11b + Ly 6 G + MDSC表型。重要的是，我们确定了粒细胞集落刺激因子（G-CSF）作为肿瘤微环境分泌的关键因子，通过STAT 3依赖性途径促进MDSC的发育。去除肿瘤来源的G-CSF减少了Gr-1+ CD 11b + MDSC的增殖和积累，并抑制肿瘤生长。这些发现强调了SOCS 3通过抑制STAT 3活化作为MDSC发育和功能的负调节剂的关键功能。
Suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway, and generally function as tumor suppressors. The absence of SOCS3 in particular leads to heightened activation of the STAT3 transcription factor, which has a striking ability to promote tumor survival while suppressing antitumor immunity. We report for the first time that genetic deletion of SOCS3 specifically in myeloid cells significantly enhances tumor growth, which correlates with elevated levels of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, and diminished CD8+ T-cell infiltration in tumors. The importance of MDSCs in promoting tumor growth is documented by reduced tumor growth upon depletion of MDSCs. Furthermore, SOCS3-deficient bone-marrow-derived cells exhibit heightened STAT3 activation and preferentially differentiate into the Gr-1+CD11b+Ly6G+ MDSC phenotype. Importantly, we identify granulocyte colony-stimulating factor (G-CSF) as a critical factor secreted by the tumor microenvironment that promotes development of MDSCs via a STAT3-dependent pathway. Abrogation of tumor-derived G-CSF reduces the proliferation and accumulation of Gr-1+CD11b+ MDSCs and inhibits tumor growth. These findings highlight the critical function of SOCS3 as a negative regulator of MDSC development and function, via inhibition of STAT3 activation.