Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy.
Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy.
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DOI：
10.1038/s41591-019-0639-4
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发表时间：
2019-11
期刊：
影响因子：
82.9
通讯作者：
Chan TA
中科院分区：
文献类型：
--
作者：
Chowell D;Krishna C;Pierini F;Makarov V;Rizvi NA;Kuo F;Morris LGT;Riaz N;Lenz TL;Chan TA
高度多态性的人类白细胞抗原I类（HLA-I）基因的功能多样性是传染病和癌症成功免疫控制的基础。发散性等位基因优势假说表明，具有两个序列更发散的等位基因的hla - 1基因型能够呈现更多样化的免疫肽。然而，hla - 1等位基因之间的序列差异（hla - 1进化的可量化指标）对免疫检查点抑制剂（ICI）治疗癌症的效果的影响仍然未知。本研究通过量化每个患者基因型hla - 1等位基因之间的理化序列差异来确定接受ICIs治疗的癌症患者的种系hla - 1进化差异（HED）。HED是ICIs治疗后生存的重要决定因素。即使在hla - 1完全杂合的患者中，高四分位数的HED患者对ICIs的反应也优于低HED患者。此外，HED强烈影响肿瘤、病毒和自身免疫肽组的多样性以及肿瘤内T细胞受体的亲和性。与肿瘤突变负荷类似，HED是主要组织相容性复合物-肽复合物多样性的基本指标，它决定了ICI的疗效。这些数据将不同的HLA等位基因优势与免疫治疗效果联系起来，并揭示了ICI反应如何依赖于HLA介导的免疫的进化效率。
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. 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 donality. 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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DOI：
10.4049/jimmunol.1700893
发表时间：
2017-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jurtz V;Paul S;Andreatta M;Marcatili P;Peters B;Nielsen M
通讯作者：
Nielsen M
DOI：
10.4049/jimmunol.1302101
发表时间：
2013-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Paul S;Weiskopf D;Angelo MA;Sidney J;Peters B;Sette A
通讯作者：
Sette A
影响因子：
32.4
作者：
Abelin JG;Keskin DB;Sarkizova S;Hartigan CR;Zhang W;Sidney J;Stevens J;Lane W;Zhang GL;Eisenhaure TM;Clauser KR;Hacohen N;Rooney MS;Carr SA;Wu CJ
通讯作者：
Wu CJ
影响因子：
3.2
作者：
Buhler S;Nunes JM;Sanchez-Mazas A
通讯作者：
Sanchez-Mazas A
影响因子：
56.9
作者：
Carrington, M;Nelson, GW;O'Brien, SJ
通讯作者：
O'Brien, SJ