人类白细胞抗原
生物
等位基因
基因型
生殖系
遗传学
免疫疗法
免疫学
癌症免疫疗法
癌症
抗原
基因
作者
Diego Chowell,Chirag Krishna,Federica Pierini,Vladimir Makarov,Naiyer A. Rizvi,Fengshen Kuo,Luc G.T. Morris,Nadeem Riaz,Tobias Lenz,Timothy A. Chan
出处
期刊:Nature Medicine
[Springer Nature]
日期:2019-11-01
卷期号:25 (11): 1715-1720
被引量:200
标识
DOI:10.1038/s41591-019-0639-4
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI