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 <i>N,N</i>-diethyl-2-[4-(2-¹⁸F-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-<i>a</i>]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. <b>Methods:</b> C57BL/6 mice (<i>n</i> = 44) orthotopically implanted with syngeneic mouse GL261 glioma cells were treated with different regimens using the CSF-1R inhibitor PLX5622 (6-fluoro-<i>N</i>-((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. <b>Results:</b> 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%). <b>Conclusion:</b> 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.