Complex Neural-Immune Interactions Shape Glioma Immunotherapy

1. Academic Background

Glioblastoma (GBM) and pediatric diffuse midline gliomas (e.g., H3K27M-mutant) are among the most aggressive tumors of the central nervous system (CNS), with limited efficacy from conventional treatments (surgery, radiotherapy, chemotherapy). For decades, the CNS was considered to have “immune privilege,” meaning the immune system could not effectively monitor the brain environment. However, recent studies have revealed a unique immune microenvironment in the CNS, including brain-border immunological niches (e.g., meninges, choroid plexus, perivascular spaces) and active immune surveillance mechanisms. Yet, gliomas exploit these mechanisms to create an immunosuppressive tumor immune microenvironment (TIME) and induce systemic immunosuppression, leading to low response rates to immunotherapy. This review systematically examines the unique neural-immune interactions in the CNS and explores strategies to optimize immunotherapy for gliomas.

2. Source of the Paper

This review was authored by Kun-Wei Song, Michael Lim, and Michelle Monje from Stanford University and published in the May 2025 issue of Immunity (DOI:10.1016/j.immuni.2025.04.017). Professor Monje is a leading authority in pediatric neuro-immuno-oncology, and her team has pioneered research on glioma microenvironment interactions with neural circuits.

3. Key Arguments and Evidence

3.1 Paradigm Shift in CNS Immune Microenvironment

Argument: The traditional “immune privilege” theory has been overturned, revealing a dynamic immune surveillance network in the CNS.
- Evidence:
- Rediscovery of the glymphatic system: AQP4-mediated cerebrospinal fluid-interstitial fluid circulation delivers antigens to cervical lymph nodes (CLNs).
- Identification of brain-border immunological niches: Includes meninges (containing CNS-associated macrophages, CAMs), choroid plexus (a hub for immune cell migration), and skull bone marrow (communicating with meninges via microscopic channels).
- Clinical data: Impaired lymphatic drainage exacerbates pathology in Alzheimer’s disease, underscoring the importance of immune surveillance for brain health.

3.2 Complex Interactions Between Gliomas and the Immune System

Argument: Gliomas evade immune attack through multiple mechanisms, including local immunosuppression and systemic immune exhaustion.
- Evidence:
- Heterogeneity of tumor-associated macrophages (TAMs): In GBM, 85% are peripherally infiltrated macrophages, while 15% are microglia; H3K27M-mutant gliomas are predominantly microglial.
- Immunosuppressive factors: TGF-β upregulation reduces CD4+ T cells and impairs CD8+ T cell function.
- Systemic effects: Clinical studies show T cell sequestration in bone marrow and thymic atrophy in newly diagnosed GBM patients.

3.3 Challenges and Breakthroughs in Immunotherapy Strategies

Argument: Immunotherapy for CNS tumors must account for the unique interplay between neurons, immune cells, and tumor cells.

3.3.1 Challenges with Immune Checkpoint Inhibitors (ICIs)

• Clinical trial data:
  
  • Phase III CheckMate ⁴⁹⁸⁄₅₄₈ trials showed nivolumab failed to improve survival in GBM (regardless of MGMT methylation status).
    
  • Neoadjuvant pembrolizumab may be more effective: Preoperative use upregulates T cell-related gene expression.
    

3.3.2 Advances in CAR-T Therapy

• Target exploration:
  
  • IL13Rα2-CAR-T: One patient achieved a complete response (CR) lasting 7.5 months.
    
  • GD2-CAR-T: For H3K27M-mutant gliomas, 4 of 11 patients showed 50%–100% tumor reduction, with a median OS of 20.6 months.
    
• Delivery optimization: Intracranial administration (e.g., intracerebroventricular infusion) outperforms intravenous delivery.
  

3.3.3 Potential of Oncolytic Viruses (OVs)

• Key studies:
  
  • HSV-1-derived teserpaturev approved in Japan for recurrent GBM, with a median OS of 20.2 months in Phase III trials.
    
  • Polio-rhinovirus chimera (PVSRIPO) extended survival in recurrent GBM.
    

3.4 Neurotoxicity of Immunotherapy

Argument: CNS immunotherapy toxicity mechanisms are unique and require tailored management.
- Classification:
- Immune effector cell-associated neurotoxicity syndrome (ICANS): Linked to blood-brain barrier disruption.
- Tumor inflammation-associated neurotoxicity (TIAN): Two subtypes (mechanical compression vs. neural network dysfunction).
- Management challenges: Dexamethasone may impair CAR-T efficacy, necessitating precision anti-inflammatory strategies like IL-1R antagonist anakinra.

4. Research Value and Highlights

4.1 Scientific Contributions

1. Theoretical innovation: Establishes a “neural-immune-tumor” tripartite interaction framework, debunking the “immune privilege” dogma.
   
2. Clinical translation:
   
   • Proposes GD2-CAR-T as a breakthrough for pediatric diffuse midline gliomas.
     
   • Reveals OVs’ novel mechanism of activating CNS antitumor immunity via viral pathogen-associated molecular patterns (PAMPs).
     

4.2 Practical Implications

1. Combination strategies: Sequential CAR-T and OV therapy may synergistically enhance T cell infiltration.
   
2. Toxicity management: CXCR3 antagonists show potential in preventing long-term cognitive impairment from microglial activation.
   

5. Important Addenda

• Sex differences: The paper notes sex-specific immune responses but calls for further mechanistic studies.
  
• Emerging technologies:
  
  • Logic-gated CAR-T to address tumor heterogeneity.
    
  • mRNA vaccines targeting mutational profiles (e.g., early clinical responses to H3K27M peptide vaccines).