Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy Academic Article uri icon

Overview

MeSH Major

  • Carcinoma
  • Drug Resistance, Neoplasm
  • Mitogen-Activated Protein Kinase Kinases
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Thyroid Neoplasms

abstract

  • CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci (A, B, and C) improved overall survival after ICB compared to patients who were homozygous for at least one HLA locus. 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-I, was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed unique elements that may impair CD8+ T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.

publication date

  • December 7, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1126/science.aao4572

PubMed ID

  • 29217585

Additional Document Info

start page

  • 1

end page

  • 13