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 invivo 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.
Highlights
The aggressiveness and molecular complexity of glioblastoma multiforme challenges the current standard care therapy, limiting the median overall survival to 14-16 months [1]
Small molecule colony stimulating factor-1 receptor (CSF-1R) inhibitors are used to study the dynamics of these cells in glioma progression and glioma-associated inflammation profiting from their ability to modulate Glioma-associated microglia/macrophages (GAMM) through a mechanism of depletion and repopulation
This study aimed to assess the suitability of a multi-tracer PET/Magnetic resonance imaging (MRI) combination to investigate the effects of microglia-depleting immunotherapy in the tumor microenvironment (TME) in a syngeneic mouse glioma model
Summary
The aggressiveness and molecular complexity of glioblastoma multiforme challenges the current standard care therapy, limiting the median overall survival to 14-16 months [1]. Targeting gliomaassociated myeloid cells represents an important strategy to develop new glioma microenvironmenttargeted therapies. These cell populations are dependent on colony stimulating factor-1 receptor (CSF-1R) signaling for their survival [5]. Glioma-associated microglia/macrophages (GAMM) are key players in creating an immunosuppressive microenvironment They can be efficiently targeted by inhibiting the colony stimulating factor-1 receptor (CSF-1R). Results: The preconditioning model (PM) indicated similar tumor growth based on MRI (44.5 ± 24.8 %), 18F-FET- (18.3 ± 11.3 %) and 18F-DPA-714-PET (16 ± 19.04 %) volume dynamics in all groups, suggesting that GAMM are not involved in glioma initiation. Conclusion: 18F-FET- and 18F-DPA-714-PET/MRI allow the non-invasive assessment of glioma growth under various regimens of CSF-1R therapy. CSF-1R-mediated modulation of GAMM may be of high interest as (co-)therapy against glioma
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