IMMU-14. TRANS-SPECIES ANALYSIS OF REPLICATION-REPAIR DEFICIENT (RRD) MEDULLOBLASTOMA AND RESPONSE TO IMMUNE CHECKPOINT INHIBITION: AN IRRDC REPORT

Abstract BACKGROUND Replication-repair deficiency (RRD) stemming from mismatch repair and polymerase proofreading gene defects (MMRD/PPD) lead to hypermutant childhood cancers, most frequently brain tumors. While medulloblastoma is reported, the clinical, genomic and immune landscape remains unknown. METHODS We analysed the genome, methylome, transcriptome (bulk, single-nuclei) and immune-microenvironment of the largest cohort of RRD-medulloblastoma patients enrolled by the International RRD Consortium and correlated these to clinical outcomes. RRD mice-models were used to preclinically assess response to immunotherapy. Results: RESULTS RRD-medulloblastoma (n=43) were enriched for anaplasia (61%) and localised disease (77%). Methylation/nano-string-based subgrouping failed to classify 40%, while the remaining clustered with the SHH-subgroup. Copy-number changes were notably infrequent (