Stephanie M. Pyonteck 1 , Leila Akkari 1 , Alberto J. Schuhmacher 1 , Robert L. Bowman 1 , Lisa Sevenich 1 , Daniela F. Quail 1 , Oakley C. Olson 1 , Marsha L. Quick 1 , Jason T. Huse 3 , 4 , Virginia Teijeiro 1 , Manu Setty 2 , Christina S. Leslie 2 , Yoko Oei 5 , Alicia Pedraza 3 , Jianan Zhang 3 , 4 , Cameron W. Brennan 3 , 4 , James C. Sutton 5 , Eric C. Holland 1 , 4 , Dylan Daniel 5 , Johanna A. Joyce 1 , 4 , #
22 September 2013
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 upon colony stimulating factor (CSF)-1 for differentiation and survival. A CSF-1R inhibitor was used to target TAMs in a mouse proneural GBM model, which dramatically 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 GM-CSF and IFN-γ facilitated TAM survival in the context of CSF-1R inhibition. Alternatively activated/ M2 macrophage markers decreased in surviving TAMs, consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in proneural GBM patients. Our results identify TAMs as a promising therapeutic target for proneural gliomas, and establish the translational potential of CSF-1R inhibition for GBM.