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MHCing the tumour’s dark genome

Nature Reviews Immunology volume 23, page 140 (2023)Cite this article

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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.

In this preprint (not peer-reviewed), Lozano-Rabella et al. show that this cryptic class of MHC class I-binding peptides is much more abundant in tumours than are neoantigens or tumour-associated antigens. Using a proteogenomics approach, they identified 517 unique, non-canonical tumour ligands (nonC-TLs) from nine tumour cell lines, mainly derived from 5′ UTRs and off-frame transcripts, some of which were found in up to five of the tumours. They detected naive T cells specific for three of the candidate nonC-TLs — 5′U-HOXC13, 5′U-ZKSCAN1 and non-coding C5orf22C — that, once expanded, could recognize multiple other tumour cell lines, thus identifying these antigens as attractive vaccine targets. Importantly, they found that although pre-existing T cell responses to nonC-TLs were not detected, thereby implying that these ligands are not involved in tumour immune surveillance, the nonC-TLs are highly immunogenic and specific to tumour cells, with little to no T cell response to healthy cells observed in their assays. However, owing to the limitations of mass spectrometry as used in this study, and other studies that have suggested that the nonC-TLs are expressed in healthy tissue, this lack of T cell response should be interpreted with caution.

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  1. Preprint Club, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Miriam Saffern & Robert Samstein

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  1. Miriam Saffern
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  2. Robert Samstein
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Correspondence to Miriam Saffern or Robert Samstein.

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Saffern, M., Samstein, R. MHCing the tumour’s dark genome. Nat Rev Immunol 23, 140 (2023). https://doi.org/10.1038/s41577-023-00839-z

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