Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-25 DOI:10.1126/sciadv.adu3461

Esther S. Ng, Gusztav Milotay, Orion Tong, Chelsea A. Taylor, Shawn Sun, Guangyi Niu, Robert Watson, Bo Sun, Sophie MacKay, James J. Gilchrist, Martin Little, Benjamin P. Fairfax, Yang Luo

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Abstract

The relationship between genetic variation and CD8⁺ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)–focused analysis of CD8⁺ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.

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在免疫检查点阻断的背景下确定CD8+ T细胞受体库的遗传决定因素

在接受免疫检查点阻断（ICB）治疗的癌症患者中，遗传变异与CD8+ T细胞受体（TCR）库使用之间的关系尚不清楚。我们进行了全基因组和人类白细胞抗原（HLA）集中的CD8+ TCR库分析，以确定ICB前后样本中可变基因（v -基因）和CDR3 k -核苷酸寡聚物使用的遗传决定因素（n = 250）。我们鉴定了11个顺式和10个反式v基因关联，主要与MHC相关，符合全基因组意义。含有HLA相关v基因的TCR克隆在整个治疗过程中不太稳定，而在单细胞水平上，基因相关克隆表现出亚群富集和肿瘤反应性表达谱的增加。值得注意的是，与hla匹配的TCR克隆患者的总生存率有所提高。我们的工作表明，在ICB治疗的背景下，基因型和TCR库之间存在复杂的关系，这对理解与治疗反应和患者预后相关的因素具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.