MHCing the tumour’s dark genome

Immune recognition of tumours is primarily thought to be driven by the presentation of tumour neoantigens — peptides derived from nonsynonymous mutations in protein-coding regions — on MHC class I molecules, which are often specific (‘private’) to an individual tumour. By contrast, other types of antigen, such as cancer germline antigens (CGAs) and melanoma-associated antigens, are shared across tumours and therefore have been leveraged as vaccine targets. However, the potential repertoire of MHC class I-bound peptides extends beyond the 2% of the genome that is known to code for functional proteins; translated products of cryptic open-reading frames, namely introns, non-coding RNA, untranslated regions (UTRs), off-frame sequences and intergenic regions, can also be presented on MHC molecules.

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