Sex, Chromosomes, and Immunity in Bladder Cancer

总体-摘要 膀胱癌（BC）在男性中的发病率是男性的3-5倍，即使调整了环境因素， 吸烟是这种疾病的主要危险因素。该计划项目补助金（PPG）的目标是推进我们的 了解BC中的“性别作为生物学变量（SABV）”，最终目标是改善患者 通过发现可用于治疗的性别特异性驱动因素，成功的基准和 该计划的影响包括确定关键的免疫学，激素，染色体，遗传学， 负责BC性别驱动生物表型的表观遗传途径，以激发新品系的设计 基于每个病人的生理性别的BC疗法。为此，PPG将联合三家领先的 实验室在各自的领域，每个解决SABV的问题，从一个独特的和互补的 专业观点：免疫学、癌症生物学/功能基因组学和表观遗传学。这三项研究 由雪松西奈医学中心癌症中心和俄亥俄州州立大学综合大学支持的团体 癌症中心，有着良好的合作历史，自2017年以来有9篇联合出版物， 正在撰写论文项目1旨在揭示BC性别差异的免疫学基础， 利用最近在CD 8 + T细胞耗竭中T细胞内源性雄激素受体信号传导的发现。 项目2将重点关注Y染色体和Y线表观遗传调节因子在驱动BC中的作用 进展和对免疫检查点阻断（ICB）的抵抗;项目3将研究肿瘤 抑制X染色体连锁表观遗传调节因子的活性以及雄激素和雌激素的作用- 依赖性激素途径，旨在阐明BC性别差异的表观遗传基础。所有三 项目将由一个行政核心（Admin Core）和两个共享资源核心（ 系统病理学核心（核心1）和数据科学核心（核心2）。Admin Core将管理和支持 通过提供行政和财政管理支持以及促进沟通， 科学互动。核心1将提供最先进的数字病理学服务，自动化和个性化 图像分析和多参数免疫监测。Core 2将提供统一的数据处理、分析 管道、数据集成、数据存储库和统计咨询。因为男性的癌症患病率 在许多其他癌症类型中观察到的发病率和死亡率，我们的科学发现可能会有广泛的 对癌症医学的影响远远超过了公元前。

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.