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

Nature Medicine volume 19, pages 1264–1272 (2013)Cite this article

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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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Figure 1: CSF-1R inhibition specifically targets macrophages, improves survival and decreases glioma malignancy in the transgenic PDG model.
Figure 2: CSF-1R inhibition blocks tumor growth and effectively regresses established gliomas.
Figure 3: Short-term BLZ945 treatment results in reduced tumor grade and proliferation and increased apoptosis.
Figure 4: BLZ945 inhibits orthotopic tumor growth of patient-derived proneural tumor spheres and cell lines in vivo.
Figure 5: CSF-1R inhibition depletes normal microglia but not TAMs in treated PDGs as a result of the production of glioma-supplied survival factors.
Figure 6: CSF-1R inhibition impairs heterotypic signaling between macrophages and glioma cells and is predictive of improved survival in patients with proneural GBM.

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Acknowledgements

We thank K. Simpson and X. Chen for excellent technical support, members of the Joyce and Holland labs, particularly T. Ozawa, K. Pitter and M. Squatrito, for technical advice and reagents and D. Chakravarti and the MSKCC Brain Tumor Center for assistance with patient and tumor sphere line information. We thank R. Benezra, K. Hunter and H.-W. Wang for reading the manuscript. We thank E. Pamer and T. Hohl (MSKCC) for providing CCR2-DTR mice and R. Lang (Cincinnati Children's Hospital Medical Center) for providing CD11b-DTR mice. We are grateful to the MSKCC Core Facilities of Genomics, Flow Cytometry and Small Animal Imaging, Geoffrey Beene Translational Oncology and the Novartis Institutes for BioMedical Research Emeryville Analytical Sciences group for technical assistance. This research was supported by US National Cancer Institute program grants of the Integrative Cancer Biology Program (CA148967; J.A.J. and C.S.L.) and Tumor Microenvironment Network (CA126518; J.A.J. and E.C.H.), Cycle for Survival (J.A.J.), the Geoffrey Beene Foundation (J.A.J., R.L.B. and O.C.O.), the MSKCC Brain Tumor Center (J.A.J. and L.A.), the Fundación Ramón Areces and Ibercaja (A.J.S.), Deutsche Forschungsgemeinschaft (L.S.), Canadian Institutes of Health Research (D.F.Q.), US National Institutes of Health T32 Institutional Research training grant (5T32GM008539, S.M.P.), US National Cancer Institute F31 fellowships (F31CA167863, R.L.B.; F31CA171384, O.C.O.) and Cornell and Gerstner Sloan Kettering graduate programs (S.M.P., R.L.B., O.C.O. and V.T.).

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  1. Stephanie M Pyonteck, Leila Akkari and Alberto J Schuhmacher: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA

    Stephanie M Pyonteck, Leila Akkari, Alberto J Schuhmacher, Robert L Bowman, Lisa Sevenich, Daniela F Quail, Oakley C Olson, Marsha L Quick, Virginia Teijeiro, Eric C Holland & Johanna A Joyce

  2. Human Oncology and Pathogenesis Program, MSKCC, New York, New York, USA

    Jason T Huse, Alicia Pedraza, Jianan Zhang & Cameron W Brennan

  3. Brain Tumor Center, MSKCC, New York, New York, USA

    Jason T Huse, Jianan Zhang, Cameron W Brennan, Eric C Holland & Johanna A Joyce

  4. Computational Biology, MSKCC, New York, New York, USA

    Manu Setty & Christina S Leslie

  5. Novartis Institutes for Biomedical Research, Emeryville, California, USA

    Yoko Oei, James C Sutton & Dylan Daniel

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Contributions

S.M.P., L.A., A.J.S., L.S., D.F.Q. and O.C.O. performed and analyzed experiments. R.L.B., M.S. and C.S.L. performed computational analyses. M.L.Q., V.T., Y.O., A.P. and J.Z. provided technical assistance or derived patient tumor sphere lines. J.T.H. performed histopathological analyses. C.W.B., J.C.S., E.C.H. and D.D. provided reagents. J.A.J. conceived, designed and supervised the study and wrote the manuscript. All authors edited or commented on the manuscript.

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Correspondence to Johanna A Joyce.

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Pyonteck, S., Akkari, L., Schuhmacher, A. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19, 1264–1272 (2013). https://doi.org/10.1038/nm.3337

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