Sex, Chromosomes, and Immunity in Bladder Cancer - 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.