Theranostics 2020; 10(4):1873-1883. doi:10.7150/thno.38659 This issue
1. Neuroradiology Department, University Hospital Heidelberg, 69120 Heidelberg, Germany.
2. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK) within the German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
3. Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4. Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
5. Division of Oncology, Department of Medicine I, Medical University of Vienna.
6. Department of Neurology, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.
Rationale: Glioblastoma is the most frequent, primary brain tumor that is characterized by a highly immunosuppressive tumor microenvironment (TME). The TME plays a key role for tumor biology and the effectiveness of immunotherapies. Composition of the TME correlates with overall survival and governs therapy response. Non invasive assessment of the TME has been notoriously difficult. Methods: We have designed an in vivo imaging approach to non invasively visualize innate immune cell dynamics in the TME in a mouse glioma model by correlated MRI and multiphoton microscopy (MR-MPM) using a bimodal, fluorescently labeled iron oxide nanoparticle (NP). The introduction of Teflon cranial windows instead of conventional Titanium rings dramatically reduced susceptibility artifacts on MRI and allowed longitudinal MR-MPM imaging for innate immune cell tracking in the same animal. Results: We visualized tumor associated macrophage and microglia (TAM) dynamics in the TME and dissect the single steps of NP uptake by blood-born monocytes that give rise to tumor-associated macrophages. Next to peripheral NP-loading, we identified a second route of direct nanoparticle uptake via the disrupted blood-brain barrier to directly label tissue resident TAMs. Conclusion: Our approach allows innate immune cell tracking by MRI and multiphoton microscopy in the same animal to longitudinally investigate innate immune cell dynamics in the TME.
Keywords: MRI, multiphoton microscopy, tumor microenvironment, tumor-associated macrophages, iron oxide nanoparticles, immunotherapy.