The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy. Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.

Another pathway to cancer resistance: Therapies targeting the tumor microenvironment show promise for treating cancer. For example, antibodies targeting colony-stimulating factor-1 receptor (CSF-1R) inhibit protumorigenic macrophages and regress tumors in mouse models of glioblastoma multiforme (GBM), a deadly form of brain cancer. Quail et al. found that although CSR-1R blockade prolonged survival in mouse models of GBM, more than 50% of tumors eventually recurred. Recurrence was correlated with elevated PI3-K activity in tumors, driven by macrophage-secreted IGF-1. Blocking PI3-K and IGF-1 signaling in rebounding tumors prolonged survival. Thus, tumors can acquire resistance to therapy through intrinsic changes and through changes in their microenvironment. Science , this issue p. 10.1126/science.aad3018