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

Hany A. Abdel-Hafiz, Johanna M. Schafer, Xingyu Chen, Tong Xiao, Timothy D. Gauntner, Zihai Li and Dan Theodorescu ()
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Hany A. Abdel-Hafiz: Cedars–Sinai Medical Center
Johanna M. Schafer: The Ohio State University Comprehensive Cancer Center–The James
Xingyu Chen: Cedars–Sinai Medical Center
Tong Xiao: The Ohio State University Comprehensive Cancer Center–The James
Timothy D. Gauntner: The Ohio State University Comprehensive Cancer Center–The James
Zihai Li: The Ohio State University Comprehensive Cancer Center–The James
Dan Theodorescu: Cedars–Sinai Medical Center

Nature, 2023, vol. 619, issue 7970, 624-631

Abstract: Abstract Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10–40% of bladder cancers1–6, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06234-x

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