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Open Access 01-12-2023 | Glioblastoma | Research

TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma

Authors: Ayse N. Menevse, Laura-Marie Ammer, Arabel Vollmann-Zwerenz, Marcell Kupczyk, Julia Lorenz, Lorraine Weidner, Abir Hussein, Julian Sax, Jasmin Mühlbauer, Nicole Heuschneider, Celine Rohrmus, Laura S. Mai, Birgit Jachnik, Slava Stamova, Valentina Volpin, Franziska C. Durst, Antonio Sorrentino, Maria Xydia, Vladimir M. Milenkovic, Stefanie Bader, Frank K. Braun, Christian Wetzel, Nathalie L. Albert, Joerg-Christian Tonn, Peter Bartenstein, Martin Proescholdt, Nils O. Schmidt, Ralf A. Linker, Markus J. Riemenschneider, Philipp Beckhove, Peter Hau

Published in: Acta Neuropathologica Communications | Issue 1/2023

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 TNFα and IFNγ. 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 TNFα and IFNγ 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.

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Title: TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma
Authors: Ayse N. Menevse
Laura-Marie Ammer
Arabel Vollmann-Zwerenz
Marcell Kupczyk
Julia Lorenz
Lorraine Weidner
Abir Hussein
Julian Sax
Jasmin Mühlbauer
Nicole Heuschneider
Celine Rohrmus
Laura S. Mai
Birgit Jachnik
Slava Stamova
Valentina Volpin
Franziska C. Durst
Antonio Sorrentino
Maria Xydia
Vladimir M. Milenkovic
Stefanie Bader
Frank K. Braun
Christian Wetzel
Nathalie L. Albert
Joerg-Christian Tonn
Peter Bartenstein
Martin Proescholdt
Nils O. Schmidt
Ralf A. Linker
Markus J. Riemenschneider
Philipp Beckhove
Peter Hau
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01550-9

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TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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