Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy
- PMID: 29217585
- PMCID: PMC6057471
- DOI: 10.1126/science.aao4572
Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy
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.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Comment in
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Response to Immune Checkpoint Blockade is Influenced by HLA-I Genotype.Cancer Discov. 2018 Feb;8(2):139. doi: 10.1158/2159-8290.CD-RW2017-236. Epub 2017 Dec 15. Cancer Discov. 2018. PMID: 29247014
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Immunotherapy: HLA genotype: good to be different.Nat Rev Immunol. 2018 Feb;18(2):78-79. doi: 10.1038/nri.2017.220. Epub 2017 Dec 27. Nat Rev Immunol. 2018. PMID: 29279611 No abstract available.
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Immunotherapy: HLA-1 genotype influences response to checkpoint inhibitors.Nat Rev Clin Oncol. 2018 Feb;15(2):66. doi: 10.1038/nrclinonc.2017.210. Epub 2018 Jan 3. Nat Rev Clin Oncol. 2018. PMID: 29297507 No abstract available.
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Enhancing responses to cancer immunotherapy.Science. 2018 Feb 2;359(6375):516-517. doi: 10.1126/science.aar6574. Epub 2018 Feb 1. Science. 2018. PMID: 29420276 No abstract available.
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