美国Cedars–Sinai医学中心Dan Theodorescu团队发现，癌症中的Y染色体缺失通过规避适应性免疫来驱动生长。这一研究成果于2023年6月21日在线发表在国际学术期刊《自然》上。

研究人员利用基因组和转录组研究报告，Y染色体缺失（LOY）与膀胱癌患者的不良预后有关。研究人员对自然发生的LOY突变的膀胱癌细胞以及通过CRISPR-Cas9靶向删除Y染色体的细胞进行了深入研究。Y阳性（Y⁺）和Y阴性（Y^-）的肿瘤在体外生长相似，而在免疫能力强的宿主中，Y^-肿瘤以T细胞依赖的方式比Y⁺肿瘤更具侵略性。高维流式细胞分析表明，Y^-肿瘤促进了肿瘤微环境中CD8⁺T细胞的明显功能障碍或耗竭。这些发现使用单核RNA测序和人类膀胱癌的空间蛋白质组学评估得到了验证。

值得注意的是，与Y⁺肿瘤相比，Y^-肿瘤在小鼠和癌症患者中都表现出对抗PD-1免疫检查点阻断疗法的反应增加。这些结果共同表明，具有LOY突变的癌细胞改变了T细胞的功能，促进了T细胞的衰竭，使其对PD-1靶向免疫疗法敏感。这项工作提供了对LOY突变的基本生物学和改善癌症免疫疗法潜在生物标志物的见解。

据介绍，LOY出现在多种癌症类型中，包括10-40%的膀胱癌，但其临床和生物学意义尚不清楚。

附：英文原文

Title: Y chromosome loss in cancer drives growth by evasion of adaptive immunity

Author: Abdel-Hafiz, Hany A., Schafer, Johanna M., Chen, Xingyu, Xiao, Tong, Gauntner, Timothy D., Li, Zihai, Theodorescu, Dan

Issue&Volume: 2023-06-21

Abstract: Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10–40% of bladder cancers1,2,3,4,5,6, but its clinical and biological significance is unknown. Here, using genomic and transcriptomic studies, we report that LOY correlates with poor prognoses in patients with bladder cancer. We performed in-depth studies of naturally occurring LOY mutant bladder cancer cells as well as those with targeted deletion of Y chromosome by CRISPR–Cas9. Y-positive (Y+) and Y-negative (Y–) tumours grew similarly in vitro, whereas Y tumours were more aggressive than Y+ tumours in immune-competent hosts in a T cell-dependent manner. High-dimensional flow cytometric analyses demonstrated that Y tumours promote striking dysfunction or exhaustion of CD8+ T cells in the tumour microenvironment. These findings were validated using single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Of note, compared with Y+ tumours, Y tumours exhibited an increased response to anti-PD-1 immune checkpoint blockade therapy in both mice and patients with cancer. Together, these results demonstrate that cancer cells with LOY mutations alter T cell function, promoting T cell exhaustion and sensitizing them to PD-1-targeted immunotherapy. This work provides insights into the basic biology of LOY mutation and potential biomarkers for improving cancer immunotherapy.

DOI: 10.1038/s41586-023-06234-x

Source: https://www.nature.com/articles/s41586-023-06234-x