Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy

Nat Med. 2019 Nov;25(11):1715-1720. doi: 10.1038/s41591-019-0639-4. Epub 2019 Nov 7.


Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes1-3. However, the effect of sequence divergence between HLA-I alleles-a quantifiable measure of HLA-I evolution-on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient's genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex-peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • Evolution, Molecular*
  • Female
  • Genes, MHC Class I / genetics*
  • Genes, MHC Class I / immunology
  • Genetic Predisposition to Disease
  • Genetic Variation / genetics*
  • Genetic Variation / immunology
  • Genotype
  • Humans
  • Immunotherapy / adverse effects
  • Male
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics


  • B7-H1 Antigen
  • CD274 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor