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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月4日

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  • 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

摘要

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.