Systemic viral vector vaccination induces brain resident memory T cells to drive anti-glioblastoma immunity

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• Glioblastoma is a fatal brain tumor resistant to current immunotherapies like immune checkpoint blockade (ICB).
• Limited T cell priming hinders effective anti-tumor immune responses in glioblastoma.
• Novel strategies are needed to initiate and sustain T cell responses against glioblastoma.

Purpose of the Study:

• To investigate the efficacy of heterologous prime-boost vaccination using ChAdOx1 and MVA in overcoming glioblastoma's immune resistance.
• To determine if vaccination can induce therapeutic anti-tumor immunity against glioblastoma.
• To characterize the phenotype and function of T cells generated by vaccination in the glioblastoma microenvironment.

Main Methods:

• Utilized a prime-boost vaccination strategy with simian adenovirus ChAdOx1 and modified vaccinia Ankara (MVA) in a murine glioblastoma model.
• Assessed therapeutic efficacy against orthotopic, ICB-refractory glioblastoma (SB28).
• Analyzed T cell infiltration, phenotype (CD103+ CD69+ CD8+ TRM-like cells), and function within tumor-challenged brains.

Main Results:

• ChAdOx1/MVA vaccination demonstrated therapeutic efficacy against glioblastoma, targeting both known (P1A) and novel (Gpr149) antigens.
• Vaccination alone was sufficient, with no added benefit from concurrent ICB.
• Systemic vaccination induced robust infiltration of antigen-specific CD8+ T cells with a tissue-resident memory (TRM)-like phenotype in the brain.
• These TRM-like cells were polyfunctional, durable, and mediated sustained tumor control and immunological memory.
• Adoptive transfer of glioblastoma-derived antigen-specific TRM-like cells conferred protection against subsequent tumor challenge.

Conclusions:

• Viral vector vaccination (ChAdOx1/MVA) effectively generates tumor-specific T cells with a TRM-like phenotype in the brain.
• This vaccination strategy mediates potent anti-glioblastoma immunity, overcoming ICB resistance.
• The findings support the clinical evaluation of ChAdOx1/MVA-based vaccination for glioblastoma treatment.