Mapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics

Mapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics

Abstract 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 o...

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Main Authors: Julia Velz, Lena K. Freudenmann, Gioele Medici, Marissa Dubbelaar, Malte Mohme, David R. Ghasemi, Jonas Scheid, Daniel J. Kowalewski, Angelica B. Patterson, Anna M. Zeitlberger, Katrin Lamszus, Manfred Westphal, Matthias Eyrich, Martina Messing-Jünger, Andreas Röhrig, Harald Reinhard, Kévin Beccaria, Rogeiro B. Craveiro, Beat M. Frey, Martin Sill, Sven Nahnsen, Marie Gauder, Konstantina Kapolou, Manuela Silginer, Tobias Weiss, Hans-Georg Wirsching, Patrick Roth, Michael Grotzer, Niklaus Krayenbühl, Oliver Bozinov, Luca Regli, Hans-Georg Rammensee, Elisabeth J. Rushing, Felix Sahm, Juliane S. Walz, Michael Weller, Marian C. Neidert
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-56268-0
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Summary:Abstract 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 map the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and perform comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma is shown to be a rich source of tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins are subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) is rare. Functional testing of top-ranking novel candidate antigens demonstrates 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 leads 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.
ISSN:2041-1723

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