MDB-21. Myc-Driven Recurrent Medulloblastoma and Cd74: Targeting the Nexus for Effective Treatment

Abstract BACKGROUND One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell communications, particularly ligand–receptor pairs, allows for the inference of significant intercellular communications based on the expression of corresponding genes. Consequently, we hypothesised that the most influential cell-cell interactions within the tumour immune microenvironment (TME) of MYC-driven MB could unveil prevalent immune-suppressive interactions and potential vulnerabilities for therapeutic exploration. METHODS/RESULTS Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. CONCLUSIONS Essential cellular interactions and therapeutic vulnerabilities have been identified in the tumour-microenvironment of MYC-driven primary-recurrent MB.