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

Chowell, D., Krishna, C., Pierini, F., Makarov, V., Rizvi, N. A., Kuo, F., et al. (2019). Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nature Medicine, 25(11), 1715-1720. doi:10.1038/s41591-019-0639-4.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-1C4F-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-1FF6-4
Genre: Journal Article

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Chowell, Diego, Author
Krishna, Chirag, Author
Pierini, Federica1, 2, Author              
Makarov, Vladimir, Author
Rizvi, Naiyer A., Author
Kuo, Fengshen, Author
Morris, Luc G. T., Author
Riaz, Nadeem, Author
Lenz, Tobias L.2, Author              
Chan, Timothy A., Author
Affiliations:
1IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445639              
2Emmy Noether Research Group Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_2616693              

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 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.

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Language(s): eng - English
 Dates: 2019-11-072019
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41591-019-0639-4
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Title: Nature Medicine
  Other : Nat. Med.
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Co.
Pages: - Volume / Issue: 25 (11) Sequence Number: - Start / End Page: 1715 - 1720 Identifier: ISSN: 1078-8956
CoNE: https://pure.mpg.de/cone/journals/resource/954925606824