Neoantigens are commonly defined as HLA-bound peptides that are altered as a consequence of DNA damage and recognized by T cells. Current efforts to target neoantigens in therapy rely on algorithms that predict HLA-binding and immunogenicity from DNA sequence data. Datasets obtained by mass spectrometry of peptides eluted from mono-allelic cell lines have greatly improved our ability to predict HLA-binding. The main challenge lies in selecting those that are likely to be immunogenic. Here we argue that the current approach of searching for antigens that have evoked T-cell responses in untreated patients may underestimate immunogenicity. Results from clinical trials show that cancer vaccines often primarily engage the naïve T-cell repertoire. We therefore propose a new pipeline where HLA-binding is detected directly by mass spectrometry and immunogenicity is determined as the ability to prime naïve T cells from healthy donors.
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