Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution

Abstract

Various cellular sources hamper interpretation of positron-emission-tomography (PET) biomarkers in the tumor microenvironment (TME). We developed immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) in combination with 3D-histology via tissue clearing to dissect the cellular allocation of PET signals in the TME. In SB28 glioblastoma mice, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs). Cellular radiotracer uptake was validated by proteomics and confirmed for in vitro samples of patients with glioblastoma. Regional agreement between PET signals and single cell tracer uptake predicted the individual cell distribution in 3D-histology. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma, however proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D-histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM-specific radioligands.

Competing Interest Statement

NLA and MB are members of the Neuroimaging Committee of the EANM. JCT received research grants from Novocure and Munich Surgical Imaging and a speaker honorarium from Seagen. NLA received funding from Novocure. MB received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and is an advisor of Life Molecular Imaging. VCR received speaker honoraria from Novocure. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

* error in batch author import