Akkari et al. showed that ionizing radiation (IR)-mediated phenotypic changes in brain-resident microglia (MG) and monocyte-derived macrophages (MDMs) led to glioblastoma recurrence in mice. An increase in the MDM:MG ratio was observed following recurrence, however, blocking MDM infiltration only modestly improved survival. RNA sequencing revealed convergence of MG and MDM gene expression signatures during recurrence in response to IR. Targeting both MG and MDM, acute CSF-1R inhibition plus IR reversed the recurrence-specific MG/MDM phenotype, and long-term CSF-1R inhibition significantly prevented glioblastoma recurrence.
Contributed by Shishir Pant
ABSTRACT: 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.