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

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön, Germany.
5
Department of Medicine, Columbia University Medical Center, New York, NY, USA.
6
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön, Germany. lenz@post.harvard.edu.
9
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chant@mskcc.org.
10
Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chant@mskcc.org.
11
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chant@mskcc.org.
12
Weill Cornell School of Medicine, New York, NY, USA. chant@mskcc.org.

Abstract

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.

PMID:
31700181
DOI:
10.1038/s41591-019-0639-4
[Indexed for MEDLINE]

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