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

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 and Marian C. Neidert ()
Additional contact information
Julia Velz: Clinical Neuroscience Center, University Hospital and University of Zurich
Lena K. Freudenmann: University of Tübingen
Gioele Medici: Clinical Neuroscience Center, University Hospital and University of Zurich
Marissa Dubbelaar: University and University Hospital Tübingen
Malte Mohme: University Medical Center Hamburg-Eppendorf
David R. Ghasemi: German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
Jonas Scheid: University of Tübingen
Daniel J. Kowalewski: University of Tübingen
Angelica B. Patterson: Cantonal Hospital St.Gallen
Anna M. Zeitlberger: Cantonal Hospital St.Gallen
Katrin Lamszus: University Medical Center Hamburg-Eppendorf
Manfred Westphal: University Medical Center Hamburg-Eppendorf
Matthias Eyrich: University Children’s Hospital, University Medical Center, University of Würzburg
Martina Messing-Jünger: Asklepios Children’s Hospital
Andreas Röhrig: Asklepios Children’s Hospital
Harald Reinhard: Asklepios Children’s Hospital
Kévin Beccaria: APHP, Université Paris Cite
Rogeiro B. Craveiro: University Hospital of RWTH Aachen
Beat M. Frey: Swiss Red Cross
Martin Sill: German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK)
Sven Nahnsen: University of Tübingen
Marie Gauder: University of Tübingen
Konstantina Kapolou: Clinical Neuroscience Center, University Hospital and University of Zurich
Manuela Silginer: Clinical Neuroscience Center, University Hospital and University of Zurich
Tobias Weiss: Clinical Neuroscience Center, University Hospital and University of Zurich
Hans-Georg Wirsching: Clinical Neuroscience Center, University Hospital and University of Zurich
Patrick Roth: Clinical Neuroscience Center, University Hospital and University of Zurich
Michael Grotzer: University Children’s Hospital Zürich
Niklaus Krayenbühl: University Hospital and University of Zurich
Oliver Bozinov: Cantonal Hospital St.Gallen
Luca Regli: University Hospital and University of Zurich
Hans-Georg Rammensee: University of Tübingen
Elisabeth J. Rushing: University Hospital and University of Zurich
Felix Sahm: German Cancer Research Center (DKFZ)
Juliane S. Walz: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen
Michael Weller: Clinical Neuroscience Center, University Hospital and University of Zurich
Marian C. Neidert: Clinical Neuroscience Center, University Hospital and University of Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56268-0

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