TAMs Are a Potential Therapeutic Target in Glioma

The presence of tumor-associated macrophages (TAM) has been linked to increased tumor grade and poor clinical outcome in glioblastoma multiforme (GBM), suggesting that depletion or inhibition of these cells may suppress tumor growth. Colony-stimulating factor 1 receptor (CSF1R) is required for macrophage differentiation and survival, prompting Pyonteck and colleagues to investigate the therapeutic potential of CSF1R blockade in preclinical models of GBM. Treatment with BLZ945, a brain-penetrant, selective CSF1R inhibitor, specifically reduced macrophage proliferation and survival in vitro without affecting glioma cell viability. Furthermore, in a transgenic mouse model of proneural GBM driven by expression of the platelet-derived growth factor B (PDGFB) oncogene, CSF1R blockade reduced the malignant progression of GBMs and induced tumor regression in mice bearing established high-grade gliomas, resulting in prolonged survival. In addition, CSF1R inhibition impaired the intracranial growth of xenografts derived from human proneural GBM cell lines or primary patient samples. This antitumor effect was mediated by decreased tumor cell proliferation and vascularity and increased apoptosis following BLZ945 treatment. However, BLZ945 did not promote depletion of TAMs, which were protected from CSF1R inhibition by glioma-secreted factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF, also known as CSF2) and IFN-γ, that promoted TAM survival. In contrast, BLZ945 triggered downregulation of protumorigenic, alternatively activated M2 macrophage markers and enhanced the phagocytic function of glioma-derived TAMs, suggesting that CSF1R blockade–induced depolarization inhibits the tumor-promoting activity of TAMs. Indeed, BLZ945 suppressed glioma cell–TAM heterotypic signaling, resulting in decreased glioma cell proliferation. Moreover, gene signatures associated with BLZ945 treatment were predictive of increased overall survival in patients with proneural GBM, independent of macrophage numbers. These findings suggest that reeducation, rather than depletion, of macrophages in the tumor microenvironment may provide therapeutic benefit in the proneural subtype of GBM.

Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013;19:1264–72.

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