IMMU-59. HDAC inhibition enhances medulloblastoma immunogenicity and prolongs survival in preclinical models

Abstract Medulloblastoma (MB), the most common malignant pediatric brain tumor, is highly resistant to immunotherapy due to its low mutational burden, immune cell exclusion, and impaired antigen presentation, resulting in part from downregulation of major histocompatibility complex class I (MHC-I). Given the prevalence of epigenetic dysregulation in MB, we performed a targeted drug screen to identify epigenetic modulators that enhance tumor immunogenicity. We identified the pan-HDAC inhibitor quisinostat as a potent inducer of surface MHC-I and multiple immune checkpoint ligands, including PD-L1 and Galectin-9, in Group 3 MB cells. Quisinostat triggered a transcriptional program overlapping with that induced by interferon (IFN) gamma, including IFN-stimulated genes (ISGs) such as TAP1, PD-L1, and MHC-I. Quisinostat treatment of mice with orthotopic tumors acutely increased histone acetylation (H3K9ac, H3K27ac), suggesting that the drug crosses the blood brain barrier. Sustained treatment with quisinostat significantly prolonged survival in MB-bearing mice, with a markedly greater benefit in immunocompetent hosts, indicating that the drug enhances immune-mediated tumor control. Ongoing studies are aimed at profiling transcriptional responses and chromatin accessibility following quisinostat treatment to better define mechanisms of action of the drug, and to identify synergistic therapeutic combinations. These data provide a strong rationale for developing HDAC inhibitor-based combination therapies to overcome immune resistance in medulloblastoma.