Program in Immunology, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Guangzhou, China.
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Oncogene. 2017 May 25;36(21):2969-2980. doi: 10.1038/onc.2016.448. Epub 2017 Jan 16.
Accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles against achieving appropriate anti-tumor immune responses and successful tumor immunotherapy. Granulocytic MDSCs (G-MDSCs) are common in tumor-bearing hosts. However, the mechanisms regulating the development of MDSCs, especially G-MDSCs, remain poorly understood. In this report, we showed that interferon regulatory factor 7 (IRF7) plays an important role in the development of G-MDSCs, but not monocytic MDSCs. IRF7 deficiency caused significant elevation of G-MDSCs, and therefore enhanced tumor growth and metastasis in mice. IRF7 deletion did not affect the suppressive activity of G-MDSCs. Mechanistic studies showed that S100A9, a negative regulator of myeloid cell differentiation, was transrepressed by the IRF7 protein. S100A9 knockdown almost completely abrogated the effects of IRF7 deletion on G-MDSC development and tumor metastasis. Importantly, IRF7 expression levels negatively correlated with the G-MDSC frequency and tumor metastasis, as well as S100A9 expression, in cancer patients. In summary, our study demonstrated that IRF7 represents a novel regulator of G-MDSC development in cancer, which may have predictive value for tumor progression.
髓系来源抑制细胞（MDSCs）的积累是阻碍获得适当的抗肿瘤免疫反应和成功的肿瘤免疫治疗的主要障碍之一。粒细胞 MDSCs（G-MDSCs）在荷瘤宿主中很常见。然而，调节 MDSCs 发展的机制，特别是 G-MDSCs 的发展机制，仍知之甚少。在本报告中，我们表明干扰素调节因子 7（IRF7）在 G-MDSCs 的发育中起重要作用，但在单核细胞 MDSCs 中不起作用。IRF7 缺陷导致 G-MDSCs 的显著升高，从而增强了小鼠的肿瘤生长和转移。IRF7 缺失不影响 G-MDSCs 的抑制活性。机制研究表明，S100A9 是一种负向调节髓样细胞分化的蛋白，其转录受到 IRF7 蛋白的抑制。S100A9 的敲低几乎完全消除了 IRF7 缺失对 G-MDSC 发育和肿瘤转移的影响。重要的是，IRF7 的表达水平与癌症患者中 G-MDSC 的频率和肿瘤转移以及 S100A9 的表达呈负相关。总之，我们的研究表明，IRF7 是癌症中 G-MDSC 发育的一种新的调节因子，可能对肿瘤进展具有预测价值。
