美国斯隆·凯特琳纪念癌症中心Timothy A. Chan和德国马克斯·普朗克进化生物学研究所Tobias L. Lenz等研究人员，合作发现HLA I类基因型的进化差异影响肿瘤免疫治疗的疗效。这一研究成果11月7日在线发表在国际学术期刊《自然—医学》上。
研究人员通过量化每个患者基因型中I型人类白细胞抗原（HLA-1）等位基因之间的理化序列差异，揭示了接受免疫检查点抑制剂（ICI）治疗的癌症患者种系HLA-1进化差异（HED）。HED是ICI治疗后生存的重要决定因素。即使在HLA-1杂合的患者中，前四分之一HED的患者对ICI的反应也比低HED的患者更好。此外，HED强烈影响肿瘤、病毒和自身免疫肽的多样性以及肿瘤内T细胞受体的克隆性。与肿瘤突变负担相似，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等位基因优势对免疫疗法的功效相关联，并揭示了ICI反应如何依赖于HLA介导的免疫效率。
据介绍，高度多态性的I型人类白细胞抗原（HLA-1）基因的功能多样性，是传染病和癌症免疫治疗成功的基础。差异等位基因优势假设表明，具有更高差异性序列的两个HLA-1等位基因的基因型能够产生更多种免疫肽。然而，HLA-1等位基因之间序列差异（HLA-1进化的一种定量方法）对免疫检查点抑制剂（ICI）治疗癌症的功效影响仍然未知。
附：英文原文
Title: Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy
Author: Diego Chowell, Chirag Krishna, Federica Pierini, Vladimir Makarov, Naiyer A. Rizvi, Fengshen Kuo, Luc G. T. Morris, Nadeem Riaz, Tobias L. Lenz, Timothy A. Chan
Issue&Volume: 2019-11-07
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 immunopeptidomes13. However, the effect of sequence divergence between HLA-I allelesa quantifiable measure of HLA-I evolutionon 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 patients 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 complexpeptide 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. The degree of sequence divergence between patient MHC class I alleles influences the response to immune checkpoint blockade therapy independently of tumor mutational burden.
DOI: 10.1038/s41591-019-0639-4
Source:https://www.nature.com/articles/s41591-019-0639-4
Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex
本期文章：《自然—医学》：Online/在线发表
