Sex, Chromosomes, and Immunity in Bladder Cancer

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OVERALL – SUMMARY Bladder cancer (BC) is 3-5 times more common in men even when adjusted for environmental factors such as smoking, the primary risk factor for this disease. The goal of this Program Project Grant (PPG) is to advance our knowledge of “sex as a biological variable (SABV)” in BC, with the ultimate objective of improving patient outcomes by discovering sex-specific drivers that can be targeted therapeutically. Benchmarks of Success and Impact for the Program include identification of key immunological, hormonal, chromosomal, genetic, and epigenetic pathways responsible for sex-driven biological phenotypes in BC to inspire the design of a novel line of BC therapeutics based on each patient’s biological sex. To this end, the PPG will unite three leading laboratories in their respective fields, each tackling the problem of SABV from a unique and complementary standpoint of expertise: immunology, cancer biology/functional genomics, and epigenetics. These three research groups, supported by Cedars-Sinai Medical Center Cancer Center and the Ohio State University Comprehensive Cancer Center, have a proven history of collaboration, with nine joint publications since 2017 and multiple co- authored papers in the pipeline. Project 1 aims to uncover the immunological basis of sex differences in BC, taking advantage of a recent discovery in T cell intrinsic androgen receptor signaling in CD8+ T cell exhaustion. Project 2 will focus on the role of the Y chromosome and the Y-lined epigenetic regulators in driving BC progression and resistance to immune checkpoint blockade (ICB); and Project 3 will investigate tumor suppressing activity of the X chromosome-linked epigenetic regulator and the roles of androgen and estrogen- dependent sex hormone pathways, aiming to elucidate the epigenetic basis of sex differences in BC. All three Projects will be supported by an Administrative Core (Admin Core) and two shared resource Cores – the Systems Pathology Core (Core 1) and the Data Science Core (Core 2). Admin Core will manage and support the entire program by offering administrative and fiscal management support and facilitating communication and scientific interactions. Core 1 will provide state-of-the-art digital pathology services, automated and personalized image analyses, and multiparameter immune monitoring. Core 2 will provide unified data processing, analytical pipelines, data integration, data repository, and statistical consultation. Because male prevalence in cancer incidence and mortality is observed across many other cancer types, our scientific findings will likely have broad implications in cancer medicine far beyond BC.