Y chromosome loss in cancer drives growth by evasion of adaptive immunity.
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.
Nature. 2023 Jun 21 [Epub ahead of print]
Hany A Abdel-Hafiz, Johanna M Schafer, Xingyu Chen, Tong Xiao, Timothy D Gauntner, Zihai Li, Dan Theodorescu
Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-The James, Columbus, OH, USA., Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37344596
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