CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells.
CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells.
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DOI：
10.1158/0008-5472.can-16-0144
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发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
Lesniak MS
中科院分区：
文献类型：
--
作者：
Chang AL;Miska J;Wainwright DA;Dey M;Rivetta CV;Yu D;Kanojia D;Pituch KC;Qiao J;Pytel P;Han Y;Wu M;Zhang L;Horbinski CM;Ahmed AU;Lesniak MS
在许多侵袭性癌症中，例如多形性胶质母细胞瘤（GBM），进展是由调节性T细胞（Treg）和骨髓源性抑制细胞（MDSC）的积累驱动的局部免疫抑制实现的。然而，Treg和MDSC如何在各种肿瘤中募集的机制细节尚未得到很好的理解。在这里，我们报告了胶质瘤微环境中的巨噬细胞和小胶质细胞产生CCL 2，这是一种在这种疾病背景下招募CCR 4 + Treg和CCR 2 +Ly-6C+单核细胞MDSC的关键趋化因子。在小鼠神经胶质瘤中，我们建立了肿瘤衍生的CCL 20和骨保护素在诱导巨噬细胞和小胶质细胞产生CCL 2中的新作用。在CCL 2缺陷小鼠中生长的肿瘤未能最大程度地积累Treg和单核细胞MDSC。在混合骨髓嵌合体试验中，我们发现CCR 4缺陷型Treg和CCR 2缺陷型单核细胞MDSC在胶质瘤积累中有缺陷。此外，CCR 4的小分子拮抗剂的施用改善了模型中的中值存活。在GBM的临床标本中，CCL 2表达水平升高与患者总生存率降低相关。最后，我们发现CD 163阳性浸润巨噬细胞是GBM患者中CCL 2的主要来源。总的来说，我们的研究结果显示了胶质瘤细胞如何影响肿瘤微环境，以招募驱动进展的免疫抑制的有效效应物。
In many aggressive cancers, such as glioblastoma multiforme (GBM), progression is enabled by local immunosuppression driven by the accumulation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). However, the mechanistic details of how Treg and MDSC are recruited in various tumors is not yet well understood. Here we report that macrophages and microglia within the glioma microenvironment produce CCL2, a chemokine that is critical for recruiting both CCR4+ Treg and CCR2+Ly-6C+ monocytic MDSC in this disease setting. In murine gliomas, we established novel roles for tumor-derived CCL20 and osteoprotegerin in inducing CCL2 production from macrophages and microglia. Tumors grown in CCL2 deficient mice failed to maximally accrue Treg and monocytic MDSC. In mixed-bone marrow chimera assays, we found that CCR4-deficient Treg and CCR2-deficient monocytic MDSC were defective in glioma accumulation. Further, administration of a small molecule antagonist of CCR4 improved median survival in the model. In clinical specimens of GBM, elevated levels of CCL2 expression correlated with reduced overall survival of patients. Lastly, we found that CD163-positive infiltrating macrophages were a major source of CCL2 in GBM patients. Collectively, our findings show how glioma cells influence the tumor microenvironment to recruit potent effectors of immunosuppression that drive progression.