Integrated Proteogenomic Deep Sequencing and Analytics Accurately Identify Non-Canonical Peptides in Tumor Immunopeptidomes

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 that derive from annotated non-coding regions could elicit anti-tu...

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Published inbioRxiv
Main Authors Chong, Chloe, Muller, Markus, Pak, Huisong, Harnett, Dermot, Huber, Florian, Grun, Delphine, Leleu, Marion, Auger, Aymeric, Arnaud, Marion, Stevenson, Brian J, Michaux, Justine, Bilic, Ilija, Hirsekorn, Antje, Calviello, Lorenzo, Simo-Riudalbas, Laia, Planet, Evarist, Lubinski, Jan, Bryskiewicz, Marta, Wiznerowicz, Maciej, Xenarios, Ioannis, Zhang, Lin, Trono, Didier, Harari, Alexandre, Ohler, Uwe, Coukos, George, Bassani-Sternberg, Michal
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 06.09.2019
Subjects
Antigens
Cancer immunotherapy
Histocompatibility antigen HLA
Immunogenicity
Immunotherapy
Lymphocytes T
Melanoma
Peptides
Stem cells
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Summary: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 that derive 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 a combination of two MS/MS search tools. This approach results in the accurate identification of hundreds of shared and tumor-specific non-canonical HLA peptides and of an immunogenic peptide from a downstream reading frame in the melanoma stem cell marker gene ABCB5. It holds great promise for the discovery of novel cancer antigens for cancer immunotherapy.
DOI:10.1101/758680