Menevse, Ayse N. and Ammer, Laura-Marie and Vollmann-Zwerenz, Arabel and Kupczyk, Marcell and Lorenz, Julia and Weidner, Lorraine and Hussein, Abir and Sax, Julian and Muehlbauer, Jasmin and Heuschneider, Nicole and Rohrmus, Celine and Mai, Laura S. and Jachnik, Birgit and Stamova, Slava and Volpin, Valentina and Durst, Franziska C. and Sorrentino, Antonio and Xydia, Maria and Milenkovic, Vladimir M. and Bader, Stefanie and Braun, Frank K. and Wetzel, Christian and Albert, Nathalie L. and Tonn, Joerg-Christian and Bartenstein, Peter and Proescholdt, Martin and Schmidt, Nils O. and Linker, Ralf A. and Riemenschneider, Markus J. and Beckhove, Philipp and Hau, Peter (2023) TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma. ACTA NEUROPATHOLOGICA COMMUNICATIONS, 11 (1): 75. ISSN 2051-5960,
Full text not available from this repository. (Request a copy)Abstract
Glioblastoma (GB) IDH-wildtype is the most malignant primary brain tumor. It is particularly resistant to current immunotherapies. Translocator protein 18 kDa (TSPO) is upregulated in GB and correlates with malignancy and poor prognosis, but also with increased immune infiltration. Here, we studied the role of TSPO in the regulation of immune resistance of human GB cells. The role of TSPO in tumor immune resistance was experimentally determined in primary brain tumor initiating cells (BTICs) and cell lines through genetic manipulation of TSPO expression and subsequent cocultures with antigen specific cytotoxic T cells and autologous tumor-infiltrating T cells. Death inducing intrinsic and extrinsic apoptotic pathways affected by TSPO were investigated. TSPO-regulated genes mediating apoptosis resistance in BTICs were identified through gene expression analysis and subsequent functional analyses. TSPO transcription in primary GB cells correlated with CD8(+) T cell infiltration, cytotoxic activity of T cell infiltrate, expression of TNFR and IFNGR and with the activity of their downstream signalling pathways, as well as with the expression of TRAIL receptors. Coculture of BTICs with tumor reactive cytotoxic T cells or with T cell-derived factors induced TSPO up-regulation through T cell derived TNF alpha and IFN gamma. Silencing of TSPO sensitized BTICs against T cell-mediated cytotoxicity. TSPO selectively protected BTICs against TRAIL-induced apoptosis by regulating apoptosis pathways. TSPO also regulated the expression of multiple genes associated with resistance against apoptosis. We conclude that TSPO expression in GB is induced through T cell-derived cytokines TNF alpha and IFN gamma and that TSPO expression protects GB cells against cytotoxic T cell attack through TRAIL. Our data thereby provide an indication that therapeutic targeting of TSPO may be a suitable approach to sensitize GB to immune cell-mediated cytotoxicity by circumventing tumor intrinsic TRAIL resistance.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KDA TRANSLOCATOR PROTEIN; BENZODIAZEPINE-RECEPTOR; GLIOMA-CELLS; THERAPEUTIC TARGET; HUMAN ASTROCYTOMAS; EXPRESSION; APOPTOSIS; CANCER; TUMORIGENICITY; SURVIVAL; TSPO; GB; Anti-tumor immunity; Immune-resistance; TRAIL-resistance |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Neurochirurgie Medicine > Lehrstuhl für Neurologie Medicine > Abteilung für Neuropathologie Medicine > Lehrstuhl für Psychiatrie und Psychotherapie > Molekulare Neurowissenscahften Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Mar 2024 17:10 |
| Last Modified: | 07 Mar 2024 17:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59021 |
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