The immunopeptidome from a genomic perspective: establishing the non-canonical landscape of MHC class I–associated peptides

Georges Bedran, Hans-Christof Gasser, Kenneth Weke, Tongjie Wang, Dominika Bedran, Alexander Laird, Christophe Battail, Fabio Massimo Zanzotto, Catia Pesquita, Håkan Axelson, Ajitha Rajan, David J. Harrison, Aleksander Palkowski, Maciej Pawlik, Maciej Parys, J Robert. O'Neill, Paul M. Brennan, Stefan N. Symeonides, David R. Goodlett, Kevin LitchfieldRobin Fahraeus, Ted R. Hupp, Sachin Kote*, Javier A. Alfaro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Tumor antigens can emerge through multiple mechanisms, including translation of non-coding genomic regions. This non-canonical category of antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry to enable the discovery of non-canonical MHC-associated peptides (ncMAPs) from non-coding regions. Considering that the emergence of tumor antigens can also involve post-translational modifications, we included an open search component in our pipeline. Leveraging the wealth of mass spectrometry-based immunopeptidomics, we analyzed 26 MHC class I immunopeptidomic studies of 9 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant post-translational modifications, using spectral matching and controlled their false discovery rate (FDR) to 1%. Interestingly, the non-canonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 54.85%. Here, we reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targeting agents for T-cell therapies or vaccine development.
Original languageEnglish
Pages (from-to)747-762
Number of pages16
JournalCancer Immunology Research
Volume11
Issue number6
Early online date24 Mar 2023
DOIs
Publication statusPublished - 1 Jun 2023

Keywords

  • Cancer
  • Tumour antigens
  • Non-canonical MHC class I-associated peptides
  • Mass spectrometry
  • Shared antigens

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