Mapping naturally presented T-cell antigens in medulloblastoma based on integrative multi-omics [RNA-seq]
Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T-cell antigens in medulloblastoma. We mapped the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and performed comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma proved to be a rich source of novel tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins were subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) was rare. Functional testing of top-ranking novel candidate antigens demonstrated the induction of peptide-specific T-cell responses, supporting their potential for T-cell immunotherapy. This study is an in-depth mapping of naturally presented T-cell antigens in medulloblastoma. Integration of immunopeptidomics, transcriptomics, and epigenetic data led to the identification of a large set of actionable targets that can be further used for the translation into the clinical setting by facilitating the informed design of immunotherapeutic approaches to children with medulloblastoma. Overall design: RNA-seq was used to profile subgroup-specific differential expression of target antigens and to characterize the immune microenvironment of medulloblastoma patients