Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification

Celina Tretter, Niklas Andrade Krätzig, Matteo Pecoraro, Sebastian Lange, Philipp Seifert, Clara Frankenberg, Johannes Untch, Gabriela Zuleger, Mathias Wilhelm, Daniel P. Zolg, Florian S. Dreyer, Eva Bräunlein, Thomas Engleitner, Sebastian Uhrig, Melanie Boxberg, Katja Steiger, Julia Slotta-Huspenina, Sebastian Ochsenreither, Nikolas Bubnoff, Sebastian Bauer, Melanie Boerries, Philipp J. Jost, Kristina Schenck, Iska Dresing, Florian Bassermann, Helmut Friess, Daniel Reim, Konrad Grützmann, Katrin Pfütze, Barbara Klink, Evelin Schröck, Bernhard Haller, Bernhard Kuster, Matthias Mann, Wilko Weichert, Stefan Fröhling, Roland Rad, Michael Hiltensperger and Angela M. Krackhardt ()
Additional contact information
Celina Tretter: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Niklas Andrade Krätzig: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IInd Medical Department
Matteo Pecoraro: Max Plank Institute of Biochemistry
Sebastian Lange: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IInd Medical Department
Philipp Seifert: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IIIrd Medical Department
Clara Frankenberg: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IIIrd Medical Department
Johannes Untch: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IIIrd Medical Department
Gabriela Zuleger: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IIIrd Medical Department
Mathias Wilhelm: Technical University of Munich, TUM School of Life Sciences, Chair of Proteomics and Bioanalytics
Daniel P. Zolg: Technical University of Munich, TUM School of Life Sciences, Chair of Proteomics and Bioanalytics
Florian S. Dreyer: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IIIrd Medical Department
Eva Bräunlein: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, IIIrd Medical Department
Thomas Engleitner: Technical University of Munich, TUM School of Medicine, Center for Translational Cancer Research (TranslaTUM)
Sebastian Uhrig: German Cancer Consortium (DKTK), partner site Heidelberg and German Cancer Research Center (DKFZ)
Melanie Boxberg: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Katja Steiger: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Julia Slotta-Huspenina: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, Institute of Pathology
Sebastian Ochsenreither: German Cancer Consortium (DKTK), partner site Berlin and German Cancer Research Center (DKFZ)
Nikolas Bubnoff: German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ)
Sebastian Bauer: German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ)
Melanie Boerries: German Cancer Consortium (DKTK), partner site Freiburg and German Cancer Research Center (DKFZ)
Philipp J. Jost: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Kristina Schenck: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Iska Dresing: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Florian Bassermann: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Helmut Friess: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, Department of Surgery
Daniel Reim: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, Department of Surgery
Konrad Grützmann: German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ)
Katrin Pfütze: German Cancer Consortium (DKTK), partner site Heidelberg and German Cancer Research Center (DKFZ)
Barbara Klink: German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ)
Evelin Schröck: German Cancer Consortium (DKTK), partner site Dresden and German Cancer Research Center (DKFZ)
Bernhard Haller: Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, Institute of AI and Informatics in Medicine
Bernhard Kuster: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Matthias Mann: Max Plank Institute of Biochemistry
Wilko Weichert: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Stefan Fröhling: German Cancer Consortium (DKTK), partner site Heidelberg and German Cancer Research Center (DKFZ)
Roland Rad: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Michael Hiltensperger: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)
Angela M. Krackhardt: German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ)

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.

Date: 2023
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DOI: 10.1038/s41467-023-39570-7

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