Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes

Chloe Chong, Markus Müller, HuiSong Pak, Dermot Harnett, Florian Huber, Delphine Grun, Marion Leleu, Aymeric Auger, Marion Arnaud, Brian J. Stevenson, Justine Michaux, Ilija Bilic, Antje Hirsekorn, Lorenzo Calviello, Laia Simó-Riudalbas, Evarist Planet, Jan Lubiński, Marta Bryśkiewicz, Maciej Wiznerowicz, Ioannis Xenarios, Lin Zhang, Didier Trono, Alexandre Harari, Uwe Ohler, George Coukos and Michal Bassani-Sternberg ()
Additional contact information
Chloe Chong: University of Lausanne, Agora Center
Markus Müller: Swiss Institute of Bioinformatics
HuiSong Pak: University of Lausanne, Agora Center
Dermot Harnett: Institute for Medical Systems Biology
Florian Huber: University of Lausanne, Agora Center
Delphine Grun: École Polytechnique Fédérale de Lausanne (EPFL)
Marion Leleu: École Polytechnique Fédérale de Lausanne (EPFL)
Aymeric Auger: Centre hospitalier universitaire vaudois (CHUV)
Marion Arnaud: University of Lausanne, Agora Center
Brian J. Stevenson: Swiss Institute of Bioinformatics
Justine Michaux: University of Lausanne, Agora Center
Ilija Bilic: Institute for Medical Systems Biology
Antje Hirsekorn: Institute for Medical Systems Biology
Lorenzo Calviello: Institute for Medical Systems Biology
Laia Simó-Riudalbas: École Polytechnique Fédérale de Lausanne (EPFL)
Evarist Planet: École Polytechnique Fédérale de Lausanne (EPFL)
Jan Lubiński: International Hereditary Cancer Center, Pomeranian Medical University
Marta Bryśkiewicz: International Hereditary Cancer Center, Pomeranian Medical University
Maciej Wiznerowicz: International Institute for Molecular Oncology
Ioannis Xenarios: University of Lausanne, Agora Center
Lin Zhang: University of Pennsylvania
Didier Trono: École Polytechnique Fédérale de Lausanne (EPFL)
Alexandre Harari: University of Lausanne, Agora Center
Uwe Ohler: Institute for Medical Systems Biology
George Coukos: University of Lausanne, Agora Center
Michal Bassani-Sternberg: University of Lausanne, Agora Center

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: Abstract Efforts to precisely identify tumor human leukocyte antigen (HLA) bound peptides capable of mediating T cell-based tumor rejection still face important challenges. Recent studies suggest that non-canonical tumor-specific HLA peptides derived from annotated non-coding regions could elicit anti-tumor immune responses. However, sensitive and accurate mass spectrometry (MS)-based proteogenomics approaches are required to robustly identify these non-canonical peptides. We present an MS-based analytical approach that characterizes the non-canonical tumor HLA peptide repertoire, by incorporating whole exome sequencing, bulk and single-cell transcriptomics, ribosome profiling, and two MS/MS search tools in combination. This approach results in the accurate identification of hundreds of shared and tumor-specific non-canonical HLA peptides, including an immunogenic peptide derived from an open reading frame downstream of the melanoma stem cell marker gene ABCB5. These findings hold great promise for the discovery of previously unknown tumor antigens for cancer immunotherapy.

Date: 2020
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DOI: 10.1038/s41467-020-14968-9

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