Abstract
Background: 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). We employed non-invasive PET/CT-MRI using 18F-FET (amino-acid metabolism) and 18F-DPA-714 (translocator protein - TSPO) to (i) understand the role of GAMM in glioma initiation, (ii) monitor in-vivo therapy-induced GAMM depletion, and (iii) 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 PLX5622 (CSF-1R inhibitor) or vehicle, establishing a “preconditioning” and a “repopulation” model, respectively. Mice underwent longitudinal PET/CT-MR imaging. 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. The repopulation-model (RM) showed (i) significantly reduced 18F-DPA-714 uptake (-45.6 ± 18.4 %) together with (ii) significantly reduced GAMM infiltration even after repopulation, and (iii) a significantly decreased tumor volume (-54.29 ± 8.6 %) with repopulation as measured by MRI, supported by a significant reduction of 18F-FET uptake (-50.2 ± 5.3 %). 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.
Footnotes
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