Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma
A partir de l'analyse du profil moléculaire de 181 échantillons tumoraux prélevés sur des patients atteints d'un glioblastome sans mutation de l'isocitrate déshydrogénase et traité par inhibiteur de point de contrôle immunitaire, cette étude identifie les caractéristiques génomiques de la tumeur et met en évidence une association entre les caractéristiques de la tumeur (enrichissement en cellules cancéreuses surexprimant des antigènes HLA de classe I et de type mésenchymateux, infiltration élevée de lymphocytes T) et la survie
The determinants of immune checkpoint blockade (ICB) response in glioblastoma (GBM) with wild-type isocitrate dehydrogenase remain poorly understood. Here we profiled 181 ICB-treated GBM samples with bulk DNA sequencing, bulk RNA sequencing and single-nucleus RNA sequencing to investigate the genomic features associated with ICB outcomes. Baseline tumor transcriptional subtype was predictive of overall survival following ICB, with mesenchymal (MES) GBM associated with improved outcomes to ICB but not standard chemoradiation. Non-MES-associated genetic lesions, including those in PDGFRA and CDKN2A, were associated with worse survival following ICB but not standard therapy. Tumor mutational burden was not predictive of outcomes. Survival was associated with pre-ICB enrichment for MES-like malignant cells, marked by high human leukocyte antigen class I expression and greater T cell infiltration. Paired tumor analyses linked ICB exposure to outgrowth of subclones harboring lesions associated with non-MES subtypes, supporting MES-to-non-MES transition as a common trajectory of acquired resistance to ICB, distinct from standard chemoradiation.
Nature Cancer , article en libre accès, 2026