Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance

Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investig...

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Published in:Science translational medicine 2020-07, Vol.12 (552), p.1
Main Authors: Akkari, Leila, Bowman, Robert L, Tessier, Jeremy, Klemm, Florian, Handgraaf, Shanna M, de Groot, Marnix, Quail, Daniela F, Tillard, Lucie, Gadiot, Jules, Huse, Jason T, Brandsma, Dieta, Westerga, Johan, Watts, Colin, Joyce, Johanna A
Format: Article
Language:English
Subjects:
Cerebrospinal fluid
Colony-stimulating factor
Gene expression
Glioblastoma
Glioma
Macrophages
Microglia
Monocytes
Phenotypes
Radiation therapy
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Summary:Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor-1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.aaw7843