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

Macrophage subsets are dynamically altered during glioma response to radiotherapy, and their targeting delays tumor recurrence in preclinical trials. Helping macrophages battle glioblastoma Although most cancer therapies target the tumor cells themselves, the tumor microenvironment also plays a key role in patients’ outcomes. Akkari et al. examined the interaction between radiation therapy, a mainstay of treatment for the brain tumor glioblastoma, and innate immune cells in the tumor microenvironment. The authors focused on two immune cell types, brain-resident microglia and monocyte-derived macrophages, and identified radiation-induced changes in protein abundance and gene expression in both cell types. On the basis of these findings, the authors selected a pharmacological treatment that enhanced the efficacy of radiotherapy in mouse models of glioblastoma. 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.