HLA-binding properties of tumor neoepitopes in humans

Abstract

Cancer genome sequencing has enabled the rapid identification of the complete repertoire of coding sequence mutations within a patient's tumor and facilitated their use as personalized immunogens. Although a variety of techniques are available to assist in the selection of mutation-defined epitopes to be included within the tumor vaccine, the ability of the peptide to bind to patient MHC is a key gateway to peptide presentation. With advances in the accuracy of predictive algorithms for MHC class I binding, choosing epitopes on the basis of predicted affinity provides a rapid and unbiased approach to epitope prioritization. We show herein the retrospective application of a prediction algorithm to a large set of bona fide T cell-defined mutated human tumor antigens that induced immune responses, most of which were associated with tumor regression or long-term disease stability. The results support the application of this approach for epitope selection and reveal informative features of these naturally occurring epitopes to aid in epitope prioritization for use in tumor vaccines.

Figure 1

(A) The two faces of a bound peptide to the MHC and TCR molecules form a “double-sided key” that must be present in order to stimulate an antigen-specific immune response. Green--Anchor residues in the peptide that interact with MHC. Purple--Regions of the peptide that interact with the TCR surface. (B) A scatter plot of the predicted affinities of epitopes that stimulate detectable neoantigen T-cell responses, shown in Table 1. Group 1 epitopes demonstrate comparable predicted affinities of native and mutated peptides and were determined to have mutations in regions of the peptide critical for interactions with the TCR (dark purple – strong/moderate binders; light purple – weak binders). Group 2 epitopes (green) are mutated peptides with strong/moderate predicted affinity whose corresponding native peptides are not predicted to bind MHC, and were found to have mutations in the peptide residues critical for the interaction with MHC. Group 3 epitopes (grey) represent peptides where neither the native or mutated peptide are predicted to be HLA-binding peptides and may be either false negatives of the prediction algorithm or very low affinity functional epitopes.