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- Title
CSF-1R inhibition alters macrophage polarization and blocks glioma progression.
- Authors
Pyonteck, Stephanie M; Akkari, Leila; Schuhmacher, Alberto J; Bowman, Robert L; Sevenich, Lisa; Quail, Daniela F; Olson, Oakley C; Quick, Marsha L; Huse, Jason T; Teijeiro, Virginia; Setty, Manu; Leslie, Christina S; Oei, Yoko; Pedraza, Alicia; Zhang, Jianan; Brennan, Cameron W; Sutton, James C; Holland, Eric C; Daniel, Dylan; Joyce, Johanna A
- Abstract
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.
- Subjects
GLIOBLASTOMA multiforme; COLONY-stimulating factors (Physiology); MACROPHAGES; MICROGLIA; GLIOMAS; CELL differentiation; LABORATORY mice
- Publication
Nature Medicine, 2013, Vol 19, Issue 10, p1264
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3337