Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma
Year: 2026
Type: preprint
Abstract: Glioblastomas (GBMs) are uniformly fatal brain tumors resistant to immunotherapy, yet the mechanisms driving immune dysfunction remain poorly understood. Here we identify a tissue-specific mechanism of dendritic cell (DC) dysfunction contributing to GBM immune evasion. We demonstrate that while systemic immunity depends on type 1 conventional DCs (cDC1s), GBMs preferentially accumulate cDC2s with impaired antigen-presenting capacity. Further, microglia-derived GAS6 and PROS1 signaling through the AXL receptor on DCs suppresses DC activation and, critically, migration to tumor-draining lymph nodes. Pharmacologic AXL inhibition enhances DC migration and consequently anti-tumor immunity. Importantly, radiation therapy activates cDC1-mediated endogenous immune responses, which synergizes with mRNA vaccination to promote complete and durable immune-mediated tumor regression. These findings establish DC-mediated immunity as a therapeutic target in brain tumors and reveal a synergistic mechanism for combining radiation with personalized cancer vaccines. Highlights ● The GBM TME is dominated by cDC2 responses, with poor accumulation of cDC1s and blunted systemic antitumor immunity ● Microglia suppress cDC migration and activation in the CNS via AXL signaling, and AXL blockade restores DC activation and migration ● Radiation therapy reactivates cDC1-mediated endogenous immunity against GBM ● Radiation therapy and tumor antigen-targeting mRNA vaccination achieve durable tumor cures in orthotopic and autochthonous GBM models
Authors: Amy J. Wisdom, Zachary J. Rogers, Fiona Chatterjee, Yufei Cui, Lizmarie Garcia-Rivera, Heidi Temple, Nouran S. Abdelfattah, Tobias Coombs, Richard Van, Cassandra Tafuri Del Vecchio, Hin Ka So, Taylor A. Heim, Grace Wolczanski, Christopher W. Mount, Vincent L. Butty, Stuart S. Levine, Kathleen Cormier, J. Christopher Love, Susan M. Kaech, Tyler Jacks, Forest M. White, Stefani Spranger
Institutions: Harvard University, Koch Institute for Integrative Cancer Research At MIT, Mass General Brigham, Massachusetts Institute of Technology, Salk Institute for Biological Studies, Allen Institute for Immunology, Allen Institute, Broad Institute, Massachusetts General Hospital, Ragon Institute of MGH, MIT and Harvard
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213979508
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