Project Details
Projekt
The role of TSPO in T-cell immune control of glioblastoma
Subject Area
Molecular and Cellular Neurology and Neuropathology
Immunology
Immunology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 403161218
Glioblastoma (GB) is the most malignant and common type of primary brain tumor with a median survival of less than 21 months. Apart from molecular alterations, the pathogenesis of GB is largely dependent on immune escape mechanisms. Translocator protein 18 kDa (TSPO) has been used as a prognostic biomarker for GB, due to its up-regulated expression compared to normal brain and positive correlation with malignancy. Based on preliminary findings we hypothesized in the first funding period that TSPO contributes to GB progression by protecting brain tumor initiating cells (BTICs) against rejection by the immune system. We demonstrated that TSPO is induced in BTICs upon their contact with tumor-reactive T-cells and T-cell derived factors. We could identify T-cell derived IFNγ and TNFα as the main inducers of TSPO in BTICs. We could also confirm IFNγ- and TNFα-mediated pathways as major causes of TSPO expression in primary human GB situ by analyzing single-cell RNA-Seq data set from primary GB samples. In regard to its` role in immune resistance of GB we demonstrated that downregulation of TSPO sensitized GB cell lines and BTICs against T cell-mediated cytotoxicity and impaired the migratory capacity of BTICs. We also found that TSPO protects BTICs selectively against TRAIL-induced apoptosis. In accordance, experimental regulation of TSPO activity by synthetic TSPO ligands consistently increased the pro-apoptotic effects of TRAIL and impaired mitochondrial activity. Transcriptome expression analysis on TSPO+/- BTICs revealed differentially expressed genes controlled by TSPO that were associated with apoptosis-resistance, stemness features, and induction of therapy-resistant mesenchymal characteristics in BTICs. Within the second funding period, our first aim is to unravel the mechanisms how TSPO orchestrates stemness and resistance against immune cell induced apoptosis in GB and thereby induces the formation of a treatment-resistant GB phenotype. Here, we will particularly study the relative impact of stemness- and anti-apoptotic driving genes regulated by TSPO compared to direct effects of TSPO on mitochondrial and extrinsic apoptosis regulation. To this end, we will also investigate how TSPO affects the accessibility of regulatory elements within the DNA. Second, we will study the relevance of TSPO in immune resistance of GB in vivo by investigating tumor rejection and immune infiltration as well as resistance against experimental immunotherapy with CAR T-cells in two syngeneic mouse models. Finally, we will use the results generated in our in vitro and in vivo models to develop translational strategies to revert immune resistance exerted by TSPO in GB. Overall, we will continue to establish TSPO inhibition as a new means to improve efficiency of immunotherapy against GB.
DFG Programme
Research Units
