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

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. 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 PET signals and serves to validate emerging novel TAM-specific radioligands

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(VLID)329431

Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome

Bartos LM, Quach S, Zenatti V, et al. Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome. bioRxiv. 2024.Local therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults, indicating global involvement of the brain in this fatal disease. To study the impact of neuroinflammation distant of the primary tumor site on the clinical course of patients with glioblastoma, we performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma, glioma WHO 2 and healthy controls and compared signals of the non-lesion (i.e. contralateral) hemisphere. Back-translation in syngeneic glioblastoma mice was used to characterize PET alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain. Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epilepsy and poor prognosis independent of the tumor phenotype. Back-translation pinpointed myeloid cells as the source of TSPO-PET signal increases and revealed a complex immune signature comprised of joint myeloid cell activation and immunosuppression in distant brain regions. In brief, neuroinflammation within the contralateral hemisphere is associated with poor outcome in patients with newly diagnosed glioblastoma. TSPO-PET serves to detect patients with global neuroinflammation who may benefit from immunomodulatory strategies