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Published January 1, 2021 | Version v1
Journal article Open

Imaging temozolomide-induced changes in the myeloid glioma microenvironment

  • 1. Silvia
  • 2. Cristina
  • 3. Alexandra
  • 4. Wolfgang
  • 5. Michael
  • 6. Stefan
  • 7. Miranda L
  • 8. Sven
  • 9. Oliver Martin
  • 10. Rosa Maria
  • 11. Bastian
  • 12. Andreas H

Description

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [18F]FET (amino acid metabolism) and [18F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRInu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [18F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [18F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [18F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [18F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.

Notes

This work has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 831514. This Joint Undertaking received support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

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Additional details

Funding

PET3D – PET Imaging in Drug Design and Development 675417
European Commission
INMIND – Imaging of Neuroinflammation in Neurodegenerative Diseases 278850
European Commission
Immune-Image – Immune-Image: Specific Imaging of Immune Cell Dynamics Using Novel Tracer Strategies 831514
European Commission