Host miR155 promotes tumor growth through a myeloid-derived suppressor cell-dependent mechanism.
Host miR155 promotes tumor growth through a myeloid-derived suppressor cell-dependent mechanism.
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DOI：
10.1158/0008-5472.can-14-2331
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发表时间：
2015-02-01
期刊：
影响因子：
11.2
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Chen S;Wang L;Fan J;Ye C;Dominguez D;Zhang Y;Curiel TJ;Fang D;Kuzel TM;Zhang B
MIR-155是一种免疫细胞发育和功能的调节剂，通常被认为具有免疫刺激作用。然而，我们在这里报告了miR-155的遗传消融使小鼠对化学致癌和几个移植瘤的生长具有抵抗力，这表明miR-155在免疫抑制和肿瘤促进中发挥作用。宿主miR-155缺陷促进了整体抗肿瘤免疫，尽管发现miR-155缺陷的树突状细胞和抗肿瘤T细胞反应不良。对免疫细胞隔间的进一步分析表明，miR-155调节功能髓系衍生抑制细胞(MDSC)在肿瘤微环境中的积累。具体地说，miR-155至少通过两种机制介导MDSC抑制活性，包括SOCS1抑制和许可生成CD4+Foxp3+调节性T细胞(Treg)的能力降低。重要的是，我们证明了miR-155的表达是MDSC促进肿瘤生长所必需的。因此，我们的结果揭示了miR-155在抗肿瘤免疫中的上下文功能，其在MDSC支持中的作用似乎在荷瘤宿主中占主导地位。总体而言，这些细胞效应的平衡似乎是miR-155促进或抑制肿瘤生长的根本决定因素。
miR-155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR-155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR-155 functions in immunosuppression and tumor promotion. Host miR-155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR-155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR-155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR-155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4+Foxp3+ regulatory T cells (Treg). Importantly, we demonstrated that miR-155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR-155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR-155 promotes or inhibits tumor growth.