New insights and approaches for analyses of immunopeptidomes

Human leucocyte antigen (HLA) molecules play a key role in health and disease by presenting antigen to T-lymphocytes for immunosurveillance. Immunopeptidomics involves the study of the collection of peptides presented within the antigen-binding groove of HLA molecules. Identifying their nature and diversity is crucial to understanding immunosurveillance especially during infection or for the recognition and potential eradication of tumours. This review discusses recent advances in the isolation, identification, and quantitation of these peptide antigens. New informatics approaches and databases have shed light on the extent of peptide antigens derived from unconventional sources including peptides derived from transcripts associated with frame shifts, long noncoding RNA, incorrectly annotated untranslated regions, post-translational modifications, and proteasomal splicing. Several challenges remain in successful analysis of immunopeptides, yet recent developments point to unexplored biology waiting to be unravelled.