The immunopeptidome from a genomic perspective: Establishing immune-relevant regions for cancer vaccine design

Abstract

A longstanding disconnect between the growing number of MHC Class I immunopeptidomic studies and genomic medicine hinders cancer vaccine design. We develop COD-dipp to genomically map the full spectrum of detected canonical and non canonical (non-exonic) MHC Class I antigens from 26 cancer studies. We demonstrate that patient mutations in regions overlapping physically identified antigens better predict immunotherapy response when compared to neoantigen predictions. We suggest a vaccine design approach using 140,966 highly immune-visible regions of the genome annotated by their expression and haplotype frequency in the human population. These regions tend to be highly conserved, mutated in cancer and harbor 7.8 times more immunogenicity. Intersecting pan-cancer mutations with these immune surveilled regions revealed a potential to create off-the-shelf multi-epitope vaccines against public neoantigens. Here we release COD-dipp, a cancer vaccine toolkit as a web-application (www.proteogenomics.ca/codipp) and open-source high-throughput resource (upon peer-review).

The Immunopeptidomics Ontology (ImPO)

“…The complexity and specificity of the domain are apparent in concepts such as the HLA, the class of proteins that present peptides on the surface of cells as part of the immune system and the very foundation of the immunopeptidomics domain. Immunopeptidomics studies focus not only on characterizing the peptides presented by the HLA but also on inferring on which of the six possible HLA alleles each peptide was presented, based on sequence motifs ( 65 ). Thus, in our model, HLA is associated with a ‘motif’ which is derived from several ‘peptides’ but also directly associated with ‘sample’, to mirror the experimental data (even though a connection to ‘sample’ could be made indirectly from the ‘peptide’ as detailed in the previous example).…”

“…The novelty and rapid evolution of immunopeptidomics are evidenced in the concept of ‘Epitope Contig’, an emerging concept recently introduced by the International Centre for Cancer Vaccine Science team in Bedran et al . ( 65 ) to mean genomic regions with ‘mutations that overlap with highly immune-visible regions’ also called ‘genomic immune clusters’. During the conceptual design of ImPO, the definition of this concept was iteratively refined to ‘A proposed region on the human genome surveyed by the immune system at a high frequency’.…”

“…The datasets corresponded to healthy and tumor conditions and were derived from cell culture, tissue and mixed sources ( Table 1 ). The data were downloaded as raw files (containing raw spectra), and they were later processed through an in-house pipeline ( 65 ) to convert them into the Mascot generic file and mzML formats, which contained mass-to-charge and intensity/abundance data about each spectrum from the raw file. The total size of all datasets was 5.8 terabytes and was organized by PRIDE/MassIVE study id (the primary level) and sample/tissue (as the secondary/sub-level).…”

“…The processed immunopeptidomics data was distributed into several files, 10 of which were relevant to the design of ImPO and are listed in Table 2 . More information about the source data is available in ( 65 ). (The listed datasets listed have also been uploaded onto a Figshare repository accessible through the URL Figshare repository named ‘ImPo Table 2 Datasets’: https://figshare.com/s/69e32bea6c69055d7693 .)…”