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

By S. Pyonteck, Leila Akkari, A. J. Schuhmacher, Robert L. Bowman, L. Sevenich, D. Quail, O. Olson, M. Quick, Jason T. Huse, Virginia Teijeiro and 10 more. Nature Medicine, 2013

2,206 citations recorded by the source corpus.

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.

Subfields: Genetics, Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/4d79fd0d1ee81d8c7af6e001e09ca11f880a670a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. P. Murray
2. J. Joyce
3. Eric C. Holland
4. D. Quail
5. R. DePinho
6. Lisa M. Coussens

In Immunology

1. A. Mantovani
2. P. Allavena
3. Lisa M. Coussens
4. A. Sica
5. J. Joyce
6. B. Ruffell
7. D. DeNardo
8. P. Murray

In Neurology

1. A. Sica
2. P. Murray
3. J. Joyce
4. A. Mantovani
5. S. Pun
6. D. Quail
7. Heather H Gustafson
8. P. Allavena

Citations in the corpus

• Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy (2017, background): “Targeting of microglia using BLZ9445 resulted in improved survival and regression of tumors in a mouse proneural GBM model.”
• Drug resistance and combating drug resistance in cancer (2019, background): “Therefore, CSF-1 receptor (CSF-1R) has been targeted by small molecule inhibitors or antibodies in cancer treatment with promising in vivo effects([117-119]).”