PMID- 31700181 OWN - NLM STAT- MEDLINE DCOM- 20200120 LR - 20220418 IS - 1546-170X (Electronic) IS - 1078-8956 (Print) IS - 1078-8956 (Linking) VI - 25 IP - 11 DP - 2019 Nov TI - Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. PG - 1715-1720 LID - 10.1038/s41591-019-0639-4 [doi] AB - 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 immunopeptidomes(1-3). 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. FAU - Chowell, Diego AU - Chowell D AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Krishna, Chirag AU - Krishna C AD - Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Pierini, Federica AU - Pierini F AD - Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plon, Germany. FAU - Makarov, Vladimir AU - Makarov V AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Rizvi, Naiyer A AU - Rizvi NA AD - Department of Medicine, Columbia University Medical Center, New York, NY, USA. FAU - Kuo, Fengshen AU - Kuo F AUID- ORCID: 0000-0003-1797-2896 AD - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Morris, Luc G T AU - Morris LGT AUID- ORCID: 0000-0002-4417-2280 AD - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Riaz, Nadeem AU - Riaz N AD - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Lenz, Tobias L AU - Lenz TL AUID- ORCID: 0000-0002-7203-0044 AD - Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plon, Germany. lenz@post.harvard.edu. FAU - Chan, Timothy A AU - Chan TA AUID- ORCID: 0000-0002-9265-0283 AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chant@mskcc.org. AD - Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chant@mskcc.org. AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. chant@mskcc.org. AD - Weill Cornell School of Medicine, New York, NY, USA. chant@mskcc.org. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 CA205426/CA/NCI NIH HHS/United States GR - R35 CA232097/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191107 PL - United States TA - Nat Med JT - Nature medicine JID - 9502015 RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) SB - IM MH - B7-H1 Antigen/antagonists & inhibitors/genetics MH - CTLA-4 Antigen/antagonists & inhibitors/genetics MH - Carcinoma, Non-Small-Cell Lung/genetics/immunology/pathology/*therapy MH - Disease-Free Survival MH - Drug Resistance, Neoplasm/genetics MH - *Evolution, Molecular MH - Female MH - Genes, MHC Class I/*genetics/immunology MH - Genetic Predisposition to Disease MH - Genetic Variation/*genetics/immunology MH - Genotype MH - Humans MH - Immunotherapy/adverse effects MH - Male MH - Programmed Cell Death 1 Receptor/antagonists & inhibitors/genetics PMC - PMC7938381 MID - NIHMS1067497 EDAT- 2019/11/09 06:00 MHDA- 2020/01/21 06:00 PMCR- 2021/03/08 CRDT- 2019/11/09 06:00 PHST- 2019/04/09 00:00 [received] PHST- 2019/10/03 00:00 [accepted] PHST- 2019/11/09 06:00 [pubmed] PHST- 2020/01/21 06:00 [medline] PHST- 2019/11/09 06:00 [entrez] PHST- 2021/03/08 00:00 [pmc-release] AID - 10.1038/s41591-019-0639-4 [pii] AID - 10.1038/s41591-019-0639-4 [doi] PST - ppublish SO - Nat Med. 2019 Nov;25(11):1715-1720. doi: 10.1038/s41591-019-0639-4. Epub 2019 Nov 7.