泌尿外科Dan Theodorescu研究组报道了癌症和T细胞中Y染色体的同时丢失会影响预后。该项研究成果发表在2025年6月4日出版的《自然》上。

研究人员试图通过对29种人类肿瘤类型的大体积和单细胞RNA测序数据进行全面的泛癌症分析，以及自体体和同基因母位模型来回答这些问题。在人和肿瘤中，恶性上皮细胞的LOY患病率最高，但肿瘤基质细胞和免疫细胞中也存在LOY，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，两者都显示免疫抑制的转录组特征。

此外，上皮细胞中LOY的大小、CD4⁺ T细胞和CD8⁺ T细胞独立预测生存，肿瘤显示并发上皮和T细胞LOY有最差的结果。

在这里，该课题组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。

据悉，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。在肿瘤中，上皮LOY也与低生存率相关。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）。

附：英文原文

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

Author: Chen, Xingyu, Shen, Yiling, Choi, Suhyeon, Abdel-Hafiz, Hany A., Basu, Mukta, Hoelzen, Lena, Tufano, Martina, Kailasam Mani, Saravana Kumar, Ranjpour, Maryam, Zhu, Jiani, Ramanujan, V. Krishnan, Koltsova, Ekaterina K., Calsavara, Vinicius F., Knott, Simon R. V., Theodorescu, Dan

Issue&Volume: 2025-06-04

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+ Tcells, with both showing transcriptomic signatures of immunosuppression. Furthermore, the magnitude of LOY in epithelial cells, CD4+ Tcells and CD8+ Tcells independently predicts survival, with tumours exhibiting concurrent epithelial and Tcell 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.

DOI: 10.1038/s41586-025-09071-2

Source: https://www.nature.com/articles/s41586-025-09071-2