Understanding Predictive Markers for Immunotherapy

Historically, identifying the clinical factors that drive ICB response in glioblastoma has been a significant challenge for neuro-oncologists. Glioblastoma with wild-type isocitrate dehydrogenase (IDH) is notoriously resistant to many standard therapies. However, recent genomic profiling of 181 samples has revealed that tumor transcriptional states play a vital role in determining survival. Researchers utilized bulk and single-nucleus RNA sequencing to map these genomic features. Specifically, they found that the mesenchymal (MES) subtype is strongly associated with improved outcomes after immune checkpoint blockade.

Furthermore, the study indicates that this survival benefit is specific to immunotherapy and does not extend to standard chemoradiation. This distinction is crucial for clinicians when selecting the most effective treatment path. Moreover, MES-like malignant cells exhibit high human leukocyte antigen (HLA) class I expression. This high expression, combined with greater T-cell infiltration, creates a more favorable environment for immune-mediated tumor clearance. Consequently, these transcriptional signatures serve as a robust predictive tool for patient stratification.

The Role of Mesenchymal States in ICB Response in Glioblastoma

In contrast to other cancers, tumor mutational burden (TMB) failed to predict survival in this glioblastoma cohort. Instead, specific genetic lesions provided more accurate prognostic information. For instance, lesions in PDGFRA and CDKN2A were associated with significantly worse survival following ICB. Additionally, the research highlighted how tumors evolve to resist treatment. Through paired tumor analyses, investigators identified a common trajectory where tumors transition from a mesenchymal to a non-mesenchymal state. As a result, resistant subclones emerge and dominate the tumor microenvironment.

Indeed, this "MES-to-non-MES" transition represents a unique mechanism of acquired resistance. This process is distinct from the resistance patterns observed in patients undergoing standard radiotherapy and chemotherapy. Therefore, monitoring these transcriptional shifts could allow for more dynamic treatment adjustments. Ultimately, these findings provide a framework for precision medicine in glioblastoma, helping doctors identify which patients will benefit most from checkpoint inhibitors.

Frequently Asked Questions

Which glioblastoma subtype responds best to ICB?

The mesenchymal (MES) subtype is associated with significantly better overall survival following immune checkpoint blockade compared to other transcriptional subtypes.

Why is TMB not a reliable predictor for glioblastoma ICB response?

Unlike many solid tumors, glioblastoma outcomes in this study were driven by specific transcriptional states and cellular infiltration rather than the total number of mutations.

What is the MES-to-non-MES transition?

This is a common trajectory of acquired resistance where the tumor shifts away from the mesenchymal subtype, allowing subclones with non-MES genetic lesions to survive treatment.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice. Refer to the latest local and national guidelines for clinical practice.

References

Ghannam JY et al. Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma. Nat Cancer. 2026 Jun 03. doi: 10.1038/s43018-026-01179-2. PMID: 42237038.

Weathers SP et al. Distinct immune-based tumor characteristics associated with longer survival in glioblastoma. Nat Commun. 2025 May 01.

Ricciuti B et al. Acquired mechanisms of resistance to PD-(L)1 blockade in solid tumors. SITC Annual Meeting Proceedings. 2022 Dec 08.