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

Human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a 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 are unknown. Here we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles and found that patients with cancer who were carrying HLA-I alleles with high peptide-binding promiscuity have significantly worse prognosis after immune checkpoint inhibition. This can be explained by a reduced capacity of the immune system to discriminate tumor neopeptides from self-peptides when patients carry highly promiscuous HLA-I variants, shifting the regulation of tumor-infiltrating T cells from activation to tolerance. In summary, HLA-I peptide-binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner, and could underlie a negative trade-off between antitumor immunity and genetic susceptibility to viral infections. Manczinger and colleagues define 'promiscuity' as a feature of HLA-I alleles representing peptide repertoire breadth; promiscuous alleles may promote a more tolerant tumor microenvironment and negatively impact tumor immune surveillance.

Automated summary

The study found that cancer patients carrying HLA-I alleles with high peptide-binding promiscuity have significantly worse prognosis after immune checkpoint inhibition. This is due to the reduced capacity of the immune system to discriminate tumor neopeptides from self-peptides in such cases, leading to a shift in the regulation of tumor-infiltrating T cells.