CSF-1R inhibition alters macrophage polarization and blocks glioma progression.
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.
1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA. [2].
Stephanie M
SM
Pyonteck
Leila
L
Akkari
Alberto J
AJ
Schuhmacher
Robert L
RL
Bowman
Lisa
L
Sevenich
Daniela F
DF
Quail
Oakley C
OC
Olson
Marsha L
ML
Quick
Jason T
JT
Huse
Virginia
V
Teijeiro
Manu
M
Setty
Christina S
CS
Leslie
Yoko
Y
Oei
Alicia
A
Pedraza
Jianan
J
Zhang
Cameron W
CW
Brennan
James C
JC
Sutton
Eric C
EC
Holland
Dylan
D
Daniel
Johanna A
JA
Joyce
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
D016186:Receptor, Macrophage Colony-Stimulating Factor