Abstract A003: Antigen-specific CD8+ T cells remodel the glioblastoma tumor microenvironment

Abstract Glioblastoma (GBM) is the most aggressive and most common form of brain cancer. The current standard of care, surgery and chemoradiation, fails to have durable clinical benefit, resulting in a 90% recurrence rate and poor survival in patients. The clinical success of immune checkpoint blockade (ICB) in several cancers has motivated their application in GBM. However, the abundant myeloid immunosuppression and low T cell infiltration in the GBM tumor microenvironment (TME) pose a significant challenge. To test this in an immunocompetent murine model, we developed the Mosaic Analysis with Dual-Recombinase mediated cassette exchange (MADR) model expressing murine epidermal growth factor receptor variant III (mEGFRvIII), loss-of-function mutations in PTEN and CDKN2A, and a minimal self-tumor antigen, hgp100. Immune assessments of orthotopic MADR-hgp100 gliomas suggest that the scarcity of tumor-infiltrating lymphocytes critically limits anti-tumor immune responses. To evaluate whether antigen-specific T cell expansion in these tumors was critical for anti-tumor immunity, we tested a novel mRNA lipid nanoparticle (mRNA-LNP) vaccine platform to drive antigen-specific T cell expansion in our MADR-hgp100 model. We utilized the adoptive transfer of small numbers of Pmel-1 T cells (∼500 cells) as a model system to track antigen-specific CD8+ T cell expansion, infiltration, and anti-tumor activity. Tumor-bearing C57BL/6 mice received naïve pmel T cells and were subsequently immunized with the gp-100-encoding mRNA-LNP. We found that vaccine-treated mice had extended survival compared to the untreated mice, correlating to a notable expansion of antigen-specific and endogenous T cells in the spleen, tumor-draining lymph nodes, and brain. Our findings highlight the efficacy of an mRNA-LNP vaccine platform in remodeling the immunosuppressive TME and boosting anti-tumor immune responses in GBM, thereby achieving a greater therapeutic effect. Citation Format: Madeline C. Ho, Julio C. Sanchez, Marissa S. Pioso, Marissa Li, Isabelle Phan, Petra Youssef, Hailey Lee, Khalid Rashid, Caius Radu, Robert M. Prins. Antigen-specific CD8+ T cells remodel the glioblastoma tumor microenvironment abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A003.