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bioRxiv · 10.1101/2020.06.25.170472

Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumour immunity

Manczinger, M.·Balogh, G.·Papp, B. T.·Koncz, B.·Asztalos, L.·Kemeny, L.·Papp, B.·Pal, C.
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Abstract

The human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a much wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response is unknown. In this paper, we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles, and found that cancer patients that carry HLA-I alleles with high peptide binding promiscuity are characterized by significantly worse prognosis after immune checkpoint inhibitor treatment. This trend can be explained by a reduced capacity of promiscuous HLA-I molecules to discriminate between human self and tumour peptides, yielding a shift in regulation of T-cells in the tumour microenvironment from activation to tolerance. In summary, HLA-I peptide binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner. It could also underlie a negative trade-off between antitumour immunity and the genetic susceptibility to viral infections.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Manczinger, M., Balogh, G., Papp, B. T., Koncz, B., Asztalos, L., Kemeny, L., Papp, B., Pal, C.. 2020-06-26. Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumour immunity. https://doi.org/10.1101/2020.06.25.170472

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