Inhibition of Colony-Stimulating Factor-1 Receptor Enhances the Efficacy of Radiotherapy and Reduces Immune Suppression in Glioblastoma

Abstract

Glioblastoma (GBM) remains an invariably fatal tumor with high rates of recurrence and progression after radiotherapy (RT). Recent evidence suggests M2 tumor associated macrophages (TAMs) play a contributory role towards the immune suppressive microenvironment of GBM and may mitigate RT-induced anti-tumor immunity. We investigated the inhibition of colony-stimulating factor-1 receptor (CSF-1R) as a potential strategy to target TAMs and improve the efficacy of RT in an immunocompetent pre-clinical GBM model. We used the CSF-1R inhibitor BLZ-945, which is currently under investigation in clinical trials as a mono-therapy for multiple solid tumors. The CSF-1R inhibitor BLZ-945 was used to examine the impact of CSF-1R inhibition on M2 polarization using in vitro assays. Then, using an orthotopic, immunocompetent murine GBM-model, mice were treated with vehicle control, RT, BLZ-945, or RT concurrently with BLZ-945. Survival and changes in the immune landscape were compared between treatment arms. BLZ-945 significantly reduced M2 polarization from bone marrow-derived monocytes in vitro. BLZ-945 alone did not result in improvement in median overall survival (mOS = 29 days) when compared to control mice (mOS = 27 days). RT led to a significant improvement in survival (mOS = 45 days; p = 0.02), while the combination of RT + BLZ-945 led to a further improvement in survival when compared to RT alone (mOS not reached; p = 0.005) with >70% of mice achieving long-term survival. Correlative studies performed on tumors resected from these mice identified a relatively large population of M2 TAMs in GBM at baseline that was further increased in response to RT. BLZ-945 mitigated the increase in M2 infiltration in response to RT. CD8 T-cells also increased significantly in response to RT. The ratio of M2 to CD8 cells was significantly lower in the BLZ-945 treated mice. Inhibition of CSF-1R with BLZ-945 improved the efficacy of RT in the treatment of GBM in a mouse model and may represent a promising strategy to improve RT-induced antitumor immune responses.