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Science. 2018 Feb 2;359(6375):582-587. doi: 10.1126/science.aao4572. Epub 2017 Dec 7.

Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
NewYork-Presbyterian/Columbia University Medical Center, 177 Fort Washington Avenue, New York, NY 10032, USA.
5
IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
6
Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065, USA.
7
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Tisch Cancer Institute, Departments of Medicine, Oncological Sciences, and Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
David Geffen School of Medicine, University of California, Los Angeles, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA.
10
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Weill Cornell School of Medicine, New York, NY 10065, USA.
12
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
13
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
14
Department of Chemistry, Columbia University, New York, NY 10027, USA.
15
NewYork-Presbyterian/Columbia University Medical Center, 177 Fort Washington Avenue, New York, NY 10032, USA. chant@mskcc.org nar2144@cumc.columbia.edu.
16
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. chant@mskcc.org nar2144@cumc.columbia.edu.

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-programmed cell death protein 1 or anti-cytotoxic T lymphocyte-associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 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 with 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 different 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.

PMID:
29217585
PMCID:
PMC6057471
DOI:
10.1126/science.aao4572
[Indexed for MEDLINE]
Free PMC Article

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