In order to determine the extent to which patient-specific human leukocyte antigen (HLA) class I genotype influences response to anti-PD-1 or anti-CTLA-4 antibodies, a group of US researchers determined the HLA class I genotype of 1,535 advanced cancer patients treated with immune checkpoint inhibitors. The results have important implications for predicting response to immune checkpoint blockade and for the design of neoantigen-based therapeutic vaccines.

To date, most research to predict clinical efficacy to immune checkpoint blockade has focused on tumor immune phenotype, somatic genomic features, or the gut microbiome, but how host germline genetics impacts response is unclear, the authors wrote in study background.

HLA class I genotype has been linked with differential immune responses to infection, inflammatory conditions, and autoimmune diseases. The antitumor activity of immune checkpoint inhibitors has been shown to depend on CD8 positive T cells, HLA class I dependent immune activity.

The study team examined two cohorts of cancer patients treated with immune checkpoint inhibitors. Cohort 1 comprised 369 patients who were treated with anti-CTLA-4 or anti-PD-1 therapy, and exome sequencing and clinical data were obtained. Within cohort 1, 269 patients had advanced melanoma and 100 patients had advanced non-small-cell lung cancer (NSCLC). Patients with NSCLC were treated mainly with anti-PD-1 monotherapy. Cohort 2 comprised 1,166 patients with different cancer types, including melanoma and NSCLC, whose tumors were subjected to targeted next-generation sequencing. These patients were treated with drugs targeting CTLA-4, PD-1/PD-L1, or a combination of both at the Memorial Sloan Kettering Cancer Center. For all patients in both cohorts, the researchers performed high-resolution HLA class I genotyping from normal DNA using DNA sequencing data or a clinically validated HLA typing assay (LabCorp).

The investigators found that maximal heterozygosity at HLA class I loci improved overall survival after immune checkpoint blockade compared to patients who were homozygous for at least one HLA locus.

In order to explore the clinical relevance, the researchers then classified each HLA class I allele into a specific supertype, based upon similar peptide-binding characteristics.

In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA class I, was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed unique elements that may impair CD8 positive T cell recognition of neoantigens.

The authors concluded their findings reveal that HLA class I genes influence patient survival to immune checkpoint inhibitors. Both patient-specific HLA class I genotype as well as somatic alterations in tumors impacted clinical outcome to immune checkpoint blockade, suggesting these factors could be considered in the design of future clinical trials. The observation that the B44 is associated with extended overall survival may provide an opportunity for the development of therapeutic vaccines that potentially target immunodominant HLA-B44-restricted neoantigens expressed by melanomas.

The findings published in Science indicate that HLA class I homozygosity and loss of heterozygosity represent a genetic barrier to effective immunotherapy, and alternative ways to harness the immune system may be necessary to maximize clinical benefit.