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

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..

HLA-I-restricted CD8+ T cell immunity may accelerate tumorigenesis in conjunction with VHL inactivation

“…Significant alleles for tumor delay were found to be B∗07:05, C∗07:01, C∗04:01, C∗05:01, C∗16:01, C∗14:02, and C∗17:01. These results are consistent with alleles that are advantageous for tumor suppression in the immune checkpoint inhibitor therapy in previous studies ( Manczinger et al., 2021 ). This finding suggests that differences in the effects of HLA alleles on tumor suppression may affect the immunosurveillance consistency of HLA zygosity.…”

‘Know thyself’ – host factors influencing cancer response to immune checkpoint inhibitors

“…They found that HLA-I promiscuity was associated with worse OS and ORR after ICI therapy, mediated by increased expression of immune tolerance genes intratumourally. This aligns with the theory that greater HLA-I promiscuity limits the ability to distinguish self epitopes versus tumour neoepitopes [53]. Once again, HLA-I promiscuity is partly informed by the variety of binding tumour neoepitopes, marrying with the concept of tumour 'immune fitness' and likely varying by tumour histology types [54].…”

Germline HLA landscape does not predict efficacy of pembrolizumab monotherapy across solid tumor types

“…As described here, we (and other groups) observed no association between germline HLA heterozygosity (at the allele or supertype level) or evolutionary divergence and clinical outcomes. Although all the methods applied attempt to capture the diversity of HLA peptide-binding potential in a given patient, none of them account for the variability in the absolute number of peptides a given HLA allele can bind (Paul et al, 2013), also known as HLA allele promiscuity (Manczinger et al, 2021). Future assessments of the impact of germline and somatic (discussed in the next section) HLA diversity may be further refined by taking into consideration the promiscuity of individual alleles.…”