2. Academic Validation
  3. CSF-1R inhibition alters macrophage polarization and blocks glioma progression

CSF-1R inhibition alters macrophage polarization and blocks glioma progression

  • Nat Med. 2013 Oct;19(10):1264-72. doi: 10.1038/nm.3337.
Stephanie M Pyonteck 1,  Leila Akkari,  Alberto J Schuhmacher,  Robert L Bowman,  Lisa Sevenich,  Daniela F Quail,  Oakley C Olson,  Marsha L Quick,  Jason T Huse,  Virginia Teijeiro,  Manu Setty,  Christina S Leslie,  Yoko Oei,  Alicia Pedraza,  Jianan Zhang,  Cameron W Brennan,  James C Sutton,  Eric C Holland,  Dylan Daniel,  Johanna A Joyce
Affiliations

Affiliation

  • 1 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA. [2].
PMID: 24056773 DOI: 10.1038/nm.3337
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.

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