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<p>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 cases using 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 <i>PDGFRA</i> and <i>CDKN2A</i>, 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.</p>

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Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma

  • 期刊论文

  • 发表日期：

    2026年6月3日

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  • Jack Y. Ghannam,
  • Julian Bryan,
  • Jakob Weiss,
  • Daniel Kovarsky,
  • David Merrell,
  • Conor Messer,
  • Kristy Schlueter-Kuck,
  • Geoffrey G. Fell,
  • Mary Jane Lim-Fat,
  • Gilbert Youssef,
  • Rifaquat Rahman,
  • Lei Qin,
  • Geoffrey S. Young,
  • J. Thomas Janes III,
  • McKayla Van Orden,
  • Kathleen L. Pfaff,
  • Andrew Gans,
  • Emma S. Lin,
  • Raymond Y. Huang,
  • Brian P. Danysh,
  • Laxmi Parida,
  • Shuqiang Li,
  • Patrick Y. Wen,
  • E. Antonio Chiocca,
  • Donna Neuberg,
  • Keith L. Ligon,
  • Itay Tirosh,
  • David A. Reardon,
  • Gad Getz,
  • Catherine J. Wu

摘要

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 cases using 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.