Having computationally identified the set of all peptides from the canonical human reference proteome that could be presented by nearly 3000 MHC class I variants (the “self-immunopeptidome”), Brown and Holt found that only about 30% of self-peptides were predicted to be presented. Self-immunopeptidome size and mutational load combined to approximate neoantigen load, which correlated with actual predicted neoantigen load and longer progression-free survival. Evidence supporting immunoediting of untreated TCGA tumors was observed and mutations in MHC-binding anchor positions appeared to confer enhanced immunogenicity.
The self-immunopeptidome is the repertoire of all self-peptides that can be presented by the combination of MHC variants carried by an individual, defined by their HLA genotype. Each MHC variant presents a distinct set of self-peptides, and the number of peptides in a set is variable. Subjects carrying MHC variants that present fewer self-peptides should also present fewer mutated peptides, resulting in decreased immune pressure on tumor cells. To explore this, we predicted peptide-MHC binding values using all unique 8-11mer human peptides in the human proteome and all available HLA class I allelic variants, for a total of 134 billion unique peptide--MHC binding predictions. From these predictions, we observe that most peptides are able to be presented by relatively few (< 250) MHC, while some can be presented by upwards of 1,500 different MHC. There is substantial overlap among the repertoires of peptides presented by different MHC and no relationship between the number of peptides presented and HLA population frequency. Nearly 30% of self-peptides are presentable by at least one MHC, leaving 70% of the human peptidome unsurveyed by T cells. We observed similar distributions of predicted self-immunopeptidome sizes in cancer subjects compared to controls, and within the pan-cancer population, predicted self-immunopeptidome size combined with mutational load to predict survival. Self-immunopeptidome analysis revealed evidence for tumor immunoediting and identified specific peptide positions that most influence immunogenicity. Because self-immunopeptidome size is defined by HLA genotypes and approximates neoantigen load, HLA genotyping could offer a rapid predictive biomarker for response to immunotherapy.