Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry

Michal Bassani-Sternberg, Eva Bräunlein, Richard Klar, Thomas Engleitner, Pavel Sinitcyn, Stefan Audehm, Melanie Straub, Julia Weber, Julia Slotta-Huspenina, Katja Specht, Marc E. Martignoni, Angelika Werner, Rüdiger Hein, Dirk H. Busch, Christian Peschel, Roland Rad, Jürgen Cox, Matthias Mann () and Angela M. Krackhardt ()
Additional contact information
Michal Bassani-Sternberg: Max Planck Institute of Biochemistry
Eva Bräunlein: Klinikum rechts der Isar, Technische Universität München
Richard Klar: Klinikum rechts der Isar, Technische Universität München
Thomas Engleitner: Klinikum rechts der Isar, Technische Universität München
Pavel Sinitcyn: Max Planck Institute of Biochemistry
Stefan Audehm: Klinikum rechts der Isar, Technische Universität München
Melanie Straub: Institute of Pathology, Technische Universität München
Julia Weber: Klinikum rechts der Isar, Technische Universität München
Julia Slotta-Huspenina: Institute of Pathology, Technische Universität München
Katja Specht: Institute of Pathology, Technische Universität München
Marc E. Martignoni: Klinikum rechts der Isar, Technische Universität München
Angelika Werner: Klinikum rechts der Isar, Technische Universität München
Rüdiger Hein: Klinikum rechts der Isar, Technische Universität München
Dirk H. Busch: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München
Christian Peschel: Klinikum rechts der Isar, Technische Universität München
Roland Rad: Klinikum rechts der Isar, Technische Universität München
Jürgen Cox: Max Planck Institute of Biochemistry
Matthias Mann: Max Planck Institute of Biochemistry
Angela M. Krackhardt: Klinikum rechts der Isar, Technische Universität München

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract Although mutations may represent attractive targets for immunotherapy, direct identification of mutated peptide ligands isolated from human leucocyte antigens (HLA) on the surface of native tumour tissue has so far not been successful. Using advanced mass spectrometry (MS) analysis, we survey the melanoma-associated immunopeptidome to a depth of 95,500 patient-presented peptides. We thereby discover a large spectrum of attractive target antigen candidates including cancer testis antigens and phosphopeptides. Most importantly, we identify peptide ligands presented on native tumour tissue samples harbouring somatic mutations. Four of eleven mutated ligands prove to be immunogenic by neoantigen-specific T-cell responses. Moreover, tumour-reactive T cells with specificity for selected neoantigens identified by MS are detected in the patient’s tumour and peripheral blood. We conclude that direct identification of mutated peptide ligands from primary tumour material by MS is possible and yields true neoepitopes with high relevance for immunotherapeutic strategies in cancer.

Date: 2016
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DOI: 10.1038/ncomms13404

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