In a research letter published on 7 November 2019 in the Nature Medicine, the investigators emphasized that similar to tumour mutation burden, HLA-I evolutionary divergence is a fundamental metric of diversity at the major histocompatibility complex–peptide complex, which dictates efficacy of immune checkpoint inhibitor therapy.
The findings came from research effort of the study team led by Tobias L. Lenz of the Max Planck Institute for Evolutionary Biology in Plön, Germany and Timothy A. Chan of the Memorial Sloan Kettering Cancer Center and Weill Cornell School of Medicine in New York, NY, USA.
The authors wrote in background that functional diversity of the highly polymorphic HLA-I genes underlies successful immunologic control in case 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 immunopeptidomes. However, the effect of sequence divergence between HLA-I alleles—a quantifiable measure of HLA-I evolution—on the efficacy of immune checkpoint inhibitor treatment for cancer remains unknown.
In the current study the germline HLA-I evolutionary divergence of patients with cancer treated with immune checkpoint inhibitors was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient’s genotype.
HLA-I evolutionary divergence was a strong determinant of survival after treatment with immune checkpoint inhibitors. Even among patients fully heterozygous at HLA-I, patients with HLA-I evolutionary divergence in the upper quartile respond better to immune checkpoint inhibitors than patients with a low HLA-I evolutionary divergence.
Furthermore, HLA-I evolutionary divergence strongly impacts the diversity of tumour, viral and self-immunopeptidomes and intratumoural T cell receptor clonality.
The authors concluded that similar to tumour mutation burden, HLA-I evolutionary divergence is a fundamental metric of diversity at the major histocompatibility complex–peptide complex, which dictates immune checkpoint inhibitor efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how immune checkpoint inhibitor response relies on the evolved efficiency of HLA-mediated immunity.
Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nature Medicine 2019; 25:1715–1720.