Histological and molecular characterization of TSPO labeling

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TSPO is frequently upregulated in neoplastically transformed tissues, including glioblastomas. This may be of use for PET imaging of brain tumors. TSPO expression is higher in IDH-wildtype glioblastomas compared to diffusely infiltrating WHO grade II and III astrocytomas. Also, the prognostically unfavorable mesenchymal glioblastoma expression subtype shows a higher TSPO expression than the classical or proneural subtype. We found that a loss of TSPO promoter methylation in glioblastoma may mechanistically drive the TSPO overexpression observed in these tumors. However, due to the heterogeneity of cell populations contributing as TSPO-PET signal source in gliomas, the imaging biomarker interpretation may be challenging. We have shown that apart from myeloid cells, glial tumor cells are a major contributor to the TSPO signal. Nevertheless, in the course of the brain tumor disease cell compositions vary, with an increasing content of reactive and resorptive changes induced under therapy. We therefore plan on a longitudinal biopsy study collecting tissue samples from primary and recurrent tumors that have been characterized for TSPO enrichment. We will then histologically and molecularly dissect the samples for TSPO expression, cell composition and RNA expression profiles. Using the novel technique of in vitro scRadiotracing we will assess TSPO expression and enrichment in parallel within the respective tissue samples. We will also perform backtranslation to disentangle TSPO tracer labeling at a cellular resolution by employing scRadiotracing in the murine SB28 model, which mimics the tumor microenvironment of human glioblastoma. Furthermore, NMRI Foxn1nu/nu mice transplanted with human primary glioblastoma cells and SB28 will be investigated by scRadiotracing for comparison of single cell TSPO enrichment in human and murine models. In order to gain a broader overview on TSPO labeling in human brain tissue, we will stain tissue microarrays that contain a spectrum of neoplastic and non-neoplastic disease states as well as non-diseased tissues from different brain regions. Bringing this information together with TSPO-PETs from respective patients/brain regions will generate a map of TSPO expression in healthy and diseased brain for clinical use. Taken together, our approach of integrating histological, molecular and imaging data will provide unique insights into TSPO-PET enrichment patterns and will help to better understand and to comprehensively describe the clinical relevance of this novel imaging biomarker.