Concurrent loss of the Y chromosome in cancer and T cells impacts outcome [scRNA-seq MB49]. Concurrent loss of the Y chromosome in cancer and T cells impacts outcome [scRNA-seq MB49]

Loss of the Y chromosome (LOY) in peripheral blood mononuclear cells (PBMCs) is the most common somatic alteration in normal men and is associated with greater mortality from epithelial cancers. In tumors, epithelial cell LOY is also associated with worse survival. This raises the fundamental question of whether a relationship between LOY in PBMCs, PBMC-derived immune cells, and cancer cells exists, and if so, what the consequences are. We addressed this through a comprehensive pan-cancer analysis of bulk and single-cell RNA sequencing data from 29 distinct human tumor types, and from autochthonous and syngeneic murine models of cancer. In both human and murine tumors, malignant epithelial cells had the highest LOY prevalence, which was associated with significant phenotypic changes. Remarkably, LOY was also found in stromal and immune cells of the tumor microenvironment (TME) of both species, with the presence of LOY in malignant epithelial cells predicting LOY in benign cells. In addition, LOY was correlated between paired tumor and PBMC samples from patients. Among benign cells, LOY drove the strongest phenotypic shift in CD4+ T and CD8+ T cells, with both showing signs of immunosuppression. The magnitudes of LOY in epithelial cells, CD4+ T cells, and CD8+ T cells were independent predictors of overall survival, with tumors exhibiting concurrent epithelial and T cell LOY having the worst outcomes. These findings provide a novel model linking LOY in immune and malignant epithelial cells and explain in part why LOY in PBMCs and tumors are both associated with greater cancer mortality. Overall design: scRNA-seq (MB49): MB49 clone 5 (C5) tumors implanted in C57Bl/6J mice (FASTQ).

外周血单核细胞（peripheral blood mononuclear cells, PBMCs）中的Y染色体缺失（Loss of Y chromosome, LOY）是健康男性体内最常见的体细胞改变，且与上皮源性癌症的更高死亡率密切相关。在肿瘤组织中，上皮细胞的LOY同样与更差的预后显著相关。这一现象引出了一个核心科学问题：PBMCs、PBMC来源的免疫细胞以及肿瘤细胞中的LOY之间是否存在关联？若存在，其具体生物学影响又是什么？
本研究通过对29种不同人类肿瘤类型的批量RNA测序与单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）数据，以及癌症自发瘤与同基因小鼠模型开展全面的泛癌分析，对上述问题进行了系统解答。在人类和小鼠肿瘤中，恶性上皮细胞的LOY检出率最高，且伴随显著的表型改变。值得注意的是，在两个物种的肿瘤微环境（tumor microenvironment, TME）的基质细胞与免疫细胞中同样检测到了LOY，且恶性上皮细胞的LOY状态可有效预测良性细胞中的LOY发生情况。
此外，患者配对的肿瘤与PBMC样本中的LOY水平呈显著正相关。在良性细胞群中，LOY对CD4+ T细胞与CD8+ T细胞的表型重塑作用最为显著，两类细胞均表现出免疫抑制相关的分子特征。上皮细胞、CD4+ T细胞及CD8+ T细胞中的LOY水平均可作为患者总生存期的独立预测因子，其中同时存在上皮细胞与T细胞LOY的肿瘤患者预后最差。
本研究提出了一个全新的模型，用以连接免疫细胞与恶性上皮细胞中的LOY，部分解释了为何PBMCs与肿瘤组织中的LOY均与更高的癌症死亡率相关。
整体实验设计：单细胞RNA测序（scRNA-seq, MB49）：将MB49克隆5（C5）细胞植入C57BL/6J小鼠体内构建的MB49肿瘤样本，其测序原始数据格式为FASTQ。