Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma.
Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma.
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DOI：
10.1158/0008-5472.can-16-2310
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发表时间：
2017-05-01
期刊：
影响因子：
11.2
通讯作者：
Hambardzumyan D
中科院分区：
文献类型：
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作者：
Chen Z;Feng X;Herting CJ;Garcia VA;Nie K;Pong WW;Rasmussen R;Dwivedi B;Seby S;Wolf SA;Gutmann DH;Hambardzumyan D
在胶质母细胞瘤（GBM）中，肿瘤相关巨噬细胞（TAM）占肿瘤块细胞的一半，包括浸润性巨噬细胞和常驻脑小胶质细胞。在努力描绘的时间和空间动态的TAM组合物在胶质瘤形成过程中，我们采用了两个基因工程小鼠模型，其中致癌驱动程序和荧光报告的单核细胞/小胶质细胞选择性Cx 3cr 1或Ccr 2启动子的控制下，分别协调表达。使用这种方法，我们证明了CX 3CR 1 LoCCR 2 Hi单核细胞被招募到胶质母细胞瘤中，在那里它们转化为CX 3CR 1HiCCR 2Lo巨噬细胞和CX 3CR 1HiCCR 2 −小胶质细胞样细胞。浸润的巨噬细胞/单核细胞占总TAM群体的约85%，而驻留的小胶质细胞占剩余的约15%。骨髓来源的浸润性巨噬细胞/单核细胞在GBM开始的早期被招募到肿瘤中，在那里它们优先定位于血管周围区域。相反，常驻小胶质细胞主要定位于肿瘤周围区域。RNA测序分析揭示了浸润和驻留细胞特有的差异基因表达模式，表明每个TAM群体具有独特的功能。值得注意的是，通过Ccl 2基因消融限制单核细胞浸润延长了荷瘤小鼠的生存期。我们的研究结果阐明了GBM中浸润和驻留髓样细胞的独特组成和功能，建立了在这种肿瘤中靶向浸润细胞的基本原理。
In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we employed two genetically engineered mouse models where oncogenic drivers and fluorescent reporters were expressed coordinately under the control of the monocyte/microglia-selective Cx3cr1 or Ccr2 promoters, respectively. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the glioblastoma, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2− microglia-like cells. Infiltrating macrophages/monocytes constituted ~85% of the total TAM population, with resident microglia accounting for the ~15% remaining. Bone marrow-derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via Ccl2 genetic ablation prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm.