Abstract A008: Engineered MHC-I Model as a Novel Platform to Decode the Glioma Immunopeptidome

Abstract High-grade brain tumors exhibit dismal survival rates, and survivors often suffer debilitating neurological side effects from standard-of-care (SoC) therapies. Recently, immunotherapies arose as potential therapeutic options for glioma. However, immunotherapies face limited efficacy, in large part due to their reliance on poorly characterized immunopeptidomes. These peptide repertoires, particularly in the most aggressive pediatric and adult brain tumors, remain largely unexplored in vivo, hindering the development of effective, tumor-specific therapies. To address this gap, we have developed a system to directly capture the in vivo tumor immunopeptidome, enabling the identification of novel immunotherapeutic targets with precise molecular characterization. To overcome these challenges, we leverage our MADR rapid tumor modeling methodology in combination with advanced immunopeptidome capturing and profiling technologies. Merging these two new platforms allow us to explore immunopeptidome landscapes obtained from modified, transgenic MHC-I within MADR models will reveal both unique and shared peptide signatures across adult and pediatric gliomas. Furthermore, this technology could be used to unravel how the peptide repertoires could be dynamically altered by tumor evolution and their standard of care treatment, providing a direct readout of how immune response and tumor progression intersect to drive recurrence. Here, we present the technology design together with its in vitro/in vivo validation of the transgenic MHC-I MADR glioma models which harboring distinct driver mutations, in order to characterize differential immunopeptidomes associated with discrete glioma tumor and immune phenotypes, including stage-specific changes. The unique and versatile design of this technology to perform this comprehensive in vivo approach will pave the way for the refinement of current immunotherapies. Hence, by empirically defining glioma-specific immunopeptidomes, we will be able to overcome the limitations of current brain tumor immunotherapies which largely rely on targets derived from other cancers or limited subsets providing a critical foundation for more effective, precise, and personalized therapeutic strategies in patients diagnosed with glioma. Citation Format: Antonio C. Fuentes-Fayos, Alberto Ayala Sarmiento, Sarah J. Parker, Joshua J. Breunig. Engineered MHC-I Model as a Novel Platform to Decode the Glioma Immunopeptidome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A008.