Cellular and molecular identity of tumor-associated macrophages in glioblastoma

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.

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