Abstract IA005: Y chromosome loss in cancer drives growth by evasion of adaptive immunity

Abstract

Abstract Loss of the Y chromosome (LOY) is observed in 10-40% of bladder cancers, but its clinical and biological significance is unknown. We will present genomic and transcriptomic studies that show LOY correlates with poor prognoses in patients. We performed studies of murine bladder cancer cells with LOY as well as those with deletion of Y chromosome by CRISPR/Cas9 and compared them to cells with and intact Y chromosome as controls. Y+ and Y- tumors grew similarly in vitro, while Y- tumors grew faster than Y+ tumors in immune competent hosts in a T cell-dependent manner. Flow cytometric analyses demonstrated that Y- tumors promote exhaustion of CD8+ T cells in the tumor microenvironment. These findings were supported by data obtained from single-nuclei RNA sequencing and spatial proteomic evaluation of human bladder cancers. Compared to Y+ tumors, Y- tumors exhibited a superior response to anti-PD-1 therapy in mice. In bladder cancer patients those with LOY tumors have better prognosis than those with Y+ tumors. This is the first evidence demonstrating that LOY in tumors alters T cell function by promoting T cell exhaustion and sensitizes them to PD-1-targeted immunotherapy. This work provides novel insights into basic LOY biology as well as the potential for the development of biomarkers for improved cancer immunotherapy. Citation Format: Dan Theodorescu. Y chromosome loss in cancer drives growth by evasion of adaptive immunity [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA005.