Concurrent loss of the Y chromosome in cancer and T cells impacts outcome

IF 50.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nature Pub Date : 2025-06-04 DOI:10.1038/s41586-025-09071-2
Xingyu Chen, Yiling Shen, Suhyeon Choi, Hany A. Abdel-Hafiz, Mukta Basu, Lena Hoelzen, Martina Tufano, Saravana Kumar Kailasam Mani, Maryam Ranjpour, Jiani Zhu, V. Krishnan Ramanujan, Ekaterina K. Koltsova, Vinicius F. Calsavara, Simon R. V. Knott, Dan Theodorescu
{"title":"Concurrent loss of the Y chromosome in cancer and T cells impacts outcome","authors":"Xingyu Chen, Yiling Shen, Suhyeon Choi, Hany A. Abdel-Hafiz, Mukta Basu, Lena Hoelzen, Martina Tufano, Saravana Kumar Kailasam Mani, Maryam Ranjpour, Jiani Zhu, V. Krishnan Ramanujan, Ekaterina K. Koltsova, Vinicius F. Calsavara, Simon R. V. Knott, Dan Theodorescu","doi":"10.1038/s41586-025-09071-2","DOIUrl":null,"url":null,"abstract":"<p>Loss of the Y chromosome (LOY) in peripheral blood mononuclear cells (PBMCs) is the most common somatic alteration in men and is associated with higher mortality from epithelial cancers<sup>1,2,3</sup>. In tumours, epithelial LOY is also associated with poor survival<sup>4,5,6,7</sup>. This raises several fundamental questions, such as why LOY in PBMCs drives cancer mortality and whether there is a relationship between LOY in PBMCs, PBMC-derived immune cells and cancer cells (and, if so, what its consequences are). We sought to answer these questions through a comprehensive pan-cancer analysis of bulk and single-cell RNA sequencing data from 29 human tumour types, along with autochthonous and syngeneic mouse models. In human and mouse tumours, malignant epithelial cells had the highest LOY prevalence, yet LOY was also present in tumour stromal and immune cells, with LOY in malignant epithelial cells predicting LOY in benign cells. LOY also correlated between paired tumour and PBMC samples from patients. Among benign cells, LOY induced the strongest shift in CD4<sup>+</sup> and CD8<sup>+</sup> T cells, with both showing transcriptomic signatures of immunosuppression. Furthermore, the magnitude of LOY in epithelial cells, CD4<sup>+</sup> T cells and CD8<sup>+</sup> T cells independently predicts survival, with tumours exhibiting concurrent epithelial and T cell LOY having the worst outcomes. Here we establish a model that links LOY in immune cells to LOY in malignant cells, which may explain in part why LOY in PBMCs is associated with increased cancer mortality.</p>","PeriodicalId":18787,"journal":{"name":"Nature","volume":"52 1","pages":""},"PeriodicalIF":50.5000,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41586-025-09071-2","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Loss of the Y chromosome (LOY) in peripheral blood mononuclear cells (PBMCs) is the most common somatic alteration in men and is associated with higher mortality from epithelial cancers1,2,3. In tumours, epithelial LOY is also associated with poor survival4,5,6,7. This raises several fundamental questions, such as why LOY in PBMCs drives cancer mortality and whether there is a relationship between LOY in PBMCs, PBMC-derived immune cells and cancer cells (and, if so, what its consequences are). We sought to answer these questions through a comprehensive pan-cancer analysis of bulk and single-cell RNA sequencing data from 29 human tumour types, along with autochthonous and syngeneic mouse models. In human and mouse tumours, malignant epithelial cells had the highest LOY prevalence, yet LOY was also present in tumour stromal and immune cells, with LOY in malignant epithelial cells predicting LOY in benign cells. LOY also correlated between paired tumour and PBMC samples from patients. Among benign cells, LOY induced the strongest shift in CD4+ and CD8+ T cells, with both showing transcriptomic signatures of immunosuppression. Furthermore, the magnitude of LOY in epithelial cells, CD4+ T cells and CD8+ T cells independently predicts survival, with tumours exhibiting concurrent epithelial and T cell LOY having the worst outcomes. Here we establish a model that links LOY in immune cells to LOY in malignant cells, which may explain in part why LOY in PBMCs is associated with increased cancer mortality.

Abstract Image

在癌症和T细胞中同时丢失Y染色体会影响结果
外周血单核细胞(pbmc)中Y染色体(LOY)的缺失是男性中最常见的体细胞改变,并与上皮性癌症的高死亡率相关1,2,3。在肿瘤中,上皮性LOY也与低生存率相关4,5,6,7。这就提出了几个基本问题,例如为什么pbmc中的LOY会导致癌症死亡率,以及pbmc中的LOY、pbmc衍生的免疫细胞和癌细胞之间是否存在关系(如果存在,其后果是什么)。我们试图通过对29种人类肿瘤类型的大细胞和单细胞RNA测序数据进行全面的泛癌症分析,以及原生和同源小鼠模型来回答这些问题。在人类和小鼠肿瘤中,恶性上皮细胞的LOY患病率最高,但LOY也存在于肿瘤基质和免疫细胞中,恶性上皮细胞的LOY可预测良性细胞的LOY。LOY在配对肿瘤和患者PBMC样本之间也存在相关性。在良性细胞中,LOY诱导CD4+和CD8+ T细胞的转移最强,两者都表现出免疫抑制的转录组特征。此外,上皮细胞、CD4+ T细胞和CD8+ T细胞中LOY的大小独立预测存活,同时表现上皮细胞和T细胞LOY的肿瘤预后最差。在这里,我们建立了一个将免疫细胞中的LOY与恶性细胞中的LOY联系起来的模型,这可能部分解释了为什么pbmc中的LOY与癌症死亡率增加相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Nature
Nature 综合性期刊-综合性期刊
CiteScore
90.00
自引率
1.20%
发文量
3652
审稿时长
3 months
期刊介绍: Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信