Abdelfattah, N. S. | Search bioRxiv

bioRxiv2026

Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma

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.

cancer biology↗

bioRxiv2026

Analysis of tumor-derived and cross-presented peptide antigens defines improved immunotherapeutic strategies

BackgroundCross-presentation of tumor antigens by antigen-presenting cells (APCs) is essential for initiating effective anti-tumor T cell immunity. The presence of cross-presenting immune cells across multiple solid tumors correlates with improved clinical outcomes. Despite the importance of this process, the identities and characteristics of tumor-derived MHC-I antigens that are cross-presented by APCs remain largely undefined, limiting rational design of targeted immunotherapies. MethodsWe performed an immunopeptidomic analysis of cross-presented glioblastoma (GBM) antigens on APCs, including bone marrow-derived macrophages, bone marrow-derived dendritic cells, and splenic dendritic cells, using SILAC labeling and in vitro co-culture systems. Additionally, we also profiled endogenous APC and tumor antigen repertoires. We made selected cross-presented antigen targets into mRNA vaccines and evaluated their immunogenicity in comparison to tumor endogenous antigens in vivo. ResultsWe identified over one thousand putative cross-presented GBM antigens. Comparative analysis of endogenous APC and tumor antigen repertoires revealed that cross-presented antigens possess distinct features and are predominantly shaped by intrinsic antigen processing and presentation pathways within APCs, resulting in limited cross-presentation of tumor-specific epitopes. Two doses of mRNA encoding cross-presented tumor-specific epitopes delayed tumor growth and elicited robust antigen-specific T cell responses. ConclusionOur findings define the landscape and constraints of tumor antigen cross-presentation in GBM and establish a framework for improved antigen selection in the development of next-generation GBM immunotherapies.

immunology↗