Interrogating Glioma-Associated Microglia and Macrophage Dynamics Under CSF-1R Therapy with Multitracer In Vivo PET/MRI.

ABSTRACT

Glioma-associated microglia and macrophages (GAMMs) are key players in creating an immunosuppressive microenvironment. They can be efficiently targeted by inhibiting the colony-stimulating factor 1 receptor (CSF-1R). We applied noninvasive PET/CT and PET/MRI using 18F-fluoroethyltyrosine (18F-FET) (amino acid metabolism) and N,N-diethyl-2-[4-(2-18F-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (18F-DPA-714) (translocator protein) to understand the role of GAMMs in glioma initiation, monitor in vivo therapy-induced GAMM depletion, and observe GAMM repopulation after drug withdrawal. Methods: C57BL/6 mice (n = 44) orthotopically implanted with syngeneic mouse GL261 glioma cells were treated with different regimens using the CSF-1R inhibitor PLX5622 (6-fluoro-N-((5-fluoro-2-methoxypyridin-3-yl)methyl)-5-((5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-amine) or vehicle, establishing a preconditioning model and a repopulation model, respectively. The mice underwent longitudinal PET/CT and PET/MRI. Results: The preconditioning model indicated similar tumor growth based on MRI (44.5% ± 24.8%), 18F-FET PET (18.3% ± 11.3%), and 18F-DPA-714 PET (16% ± 19.04%) volume dynamics in all groups, suggesting that GAMMs are not involved in glioma initiation. The repopulation model showed significantly reduced 18F-DPA-714 uptake (-45.6% ± 18.4%), significantly reduced GAMM infiltration even after repopulation, and a significantly decreased tumor volume (-54.29% ± 8.6%) with repopulation as measured by MRI, supported by a significant reduction in 18F-FET uptake (-50.2% ± 5.3%). Conclusion: 18F-FET and 18F-DPA-714 PET/MRI allow noninvasive assessment of glioma growth under various regimens of CSF-1R therapy. CSF-1R-mediated modulation of GAMMs may be of high interest as therapy or cotherapy against glioma.