Modulation of Macrophage Subpopulation Response in Radiation-Treated Gliomas Circumvents Tumor Recurrence

Thorough examination of tumor associated macrophage/microglia have shed light into their pro-tumorigenic functions in glioblastoma multiforme (GBM) development and progression. However, the dynamic evolution of these two ontogenically distinct macrophage subpopulation in the course of therapeutic response and recurrence is unknown. We employed multiple mouse models of GBM to show that infiltrating bone marrow derived macrophages (BMDM) and brain resident microglia (MG) content and phenotype are altered post radiotherapy. We identified IR specific and stage-dependent shared and distinct BMDM and MG signatures, and demonstrated that only dual targeting of these populations using CSF-1R inhibition combined with IR led to a sustained overall survival. Our findings establish that plasticity underlie macrophage evolution in the irradiated tumor microenvironment, and reveals the therapeutic potential of their targeting to enhance the efficacy of standard of care treatment in GBM. Paired Microglia (MG) and bone marrow-derived macrophages (BMDM) were isolated from Vehicle (n=4) mice or mice treated with the following condiitons: 5-days BLZ945 (n=4), 5-days BLZ945+IR (n=3), 5-days IR (n=2), recurrent BLZ945 (n=2), recurrent IR (n=4), and recurrent IR+BLZ945 (n=4). RNA was isolated and RNA-sequencing was performed to assess how BMDM and MG respond to different types of therapy in both regressing and progressing tumors,