How mutant isocitrate dehydrogenase orchestrates immune cells

• Verfasst von: Bunse, Lukas [VerfasserIn]
• Verfasst von: Platten, Michael [VerfasserIn]
• Titel: How mutant isocitrate dehydrogenase orchestrates immune cells
• Verf.angabe: Lukas Bunse and Michael Platten
• Jahr: 2022
• Umfang: 3 S.
• Fussnoten: Online veröffentlicht: 22. November 2021 ; Gesehen am 03.08.2023
• Titel Quelle: Enthalten in: Neuro-Oncology
• Ort Quelle: Oxford : Oxford Univ. Press, 1999
• Jahr Quelle: 2022
• Band/Heft Quelle: 24(2022), 2, Seite 210-212
• ISSN Quelle: 1523-5866
• DOI: doi:10.1093/neuonc/noab266
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 185429170X

Abstract

Astrocytomas and oligodendrogliomas, World Health Organization grades 2-4, are signified by recurrent mutations in the genes for mutant isocitrate dehydrogenase (IDH) types 1 and 2. The neomorphic enzymatic activity of mutant IDH causes epigenetic reprogramming by histone and DNA hypermethylation via the excessive production of the oncometabolite R-2-hydroxyglutarate (R-2-HG), ultimately driving dedifferentiation and malignant transformation. Therefore, small molecule mutant IDH inhibitors have been developed to re-differentiate glioma cells in early-stage gliomas.In recent years, a plethora of data has been collected highlighting mutant IDH as a key suppressor of spontaneous and therapy-induced anti-glioma immunity. On the one hand, mutant IDH excludes T cells from the glioma microenvironment (GME) by inhibition of glioma cell signal transducer and activator of transcription 1 (STAT1) transcriptional activity followed by reduced C-X-C motif chemokine ligand 10 (CXCL10)-dependent recruitment of cytotoxic T cells. On the other, its neomorphic enzymatic product R-2-HG incapacitates yet infiltrating T cells by paracrine inhibition of calcium-dependent T cell receptor signaling and polyamine biosynthesis and induces apoptosis of intratumoral T cells.1-3