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

Menée à l'aide de lignées cellulaires, de modèles murins et de données du projet "The Cancer Genome Atlas" portant sur 300 patients masculins atteints d'un cancer invasif de la vessie de stade localement avancé, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses ayant perdu le chromosome Y favorisent la croissance tumorale en induisant l'épuisement des lymphocytes T

Résumé en anglais

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.