Glioblastoma genetic drivers dictate the function of tumor-Associated macrophages/microglia and responses to CSF1R inhibition

Background: Tumor-Associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-Tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment (TME) conveys distinct sensitivities to TAM targeting. Methods: We generated syngeneic PDGFB-and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-Targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in TME cellular compositions and functions in PDGFB-and RAS-driven gliomas. Results: We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-Tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-Targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas. Conclusions: Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-Angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-Targeted therapy.