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Sexual Dimorphism in T Cell Exhaustion and Bladder Cancer

T 细胞耗竭和膀胱癌中的性别二态性

基本信息

批准号：
10629078
负责人：
Zihai Li
金额：
$ 53.14万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629078
关键词：
Adopted Aggressive behavior Androgen Receptor Androgens Antitumor Response Biological CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cell Proliferation Cell Survival Cellular biology Chromosomes Chronic Collaborations Data Environment Epigenetic Process Female Frequencies Functional disorder Genes Genetic Transcription Goals Gonadal Steroid Hormones Hormones Immune Immune Evasion Immune response Immunity Immunologics Immunology Immunotherapy In Vitro Incidence Knowledge Link Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Molecular Molecular Target Mus Organ Population Production Prognosis Proteins Publishing Receptor Signaling Rejuvenation Reporting Risk Factors Role Science Sex Bias Sex Chromosomes Sex Differences Signal Transduction Smoking T cell differentiation T cell response T-Cell Receptor T-Lymphocyte Tumor-Infiltrating Lymphocytes Woman Work Zinc Fingers androgen deprivation therapy anti-PD-1 anti-PD1 therapy cancer immunotherapy cancer subtypes cell type chromosome Y loss effector T cell exhaust exhaustion gene network immune checkpoint blockade immune function improved in vivo male men nuclear factors of activated T-cells progenitor programs response sex sexual dimorphism single-cell RNA sequencing transcription factor tumor tumor microenvironment tumor progression

项目摘要

PROJECT 1 – SUMMARY Sex is an understudied biological variable with significant influence on immune function, including in the context of cancer. However, the immunological mechanisms underlying the sex bias seen in cancers from non- reproductive organs, such as bladder cancer (BC), remain elusive. Male bias in BC incidence persists after adjustment for other known risk factors suggesting a fundamental biological basis for this sexual dimorphism. Objective: To define the molecular mechanisms by which androgens, AR target genes, and sex chromosome- encoded epigenetic modifiers contribute to sex differences in CD8+ T cell exhaustion in the tumor microenvironment (TME). Impact: Our study will uncover an immunological basis and mechanism by which CD8+ T cell exhaustion contributes to sex bias in BC, with implications for improving ICB approaches for all cancer via three specific aims. Aim 1: Determine the role of AR-TCF1 and AR-TOX in CD8+ T cell exhaustion and tumor control. The molecular mechanisms by which androgens influence T cells and contribute to cancer progression are unclear. Male CD8+ tumor-infiltrating lymphocytes (TILs) preferentially adopt a TCF1+ PE state due to direct activation of Tcf7 by AR. Hypothesis. Androgen signaling establishes a stable TCF1-driven transcriptional network in CD8+ T cells that favors exhaustion, through the modulation of TOX, another critical transcription factor (TF) that promotes T cell exhaustion. Aim 2: Determine the role of AR-ZFP148 in T cell effector differentiation. TF ZFP148 regulates cell proliferation and survival in non-immune cell types but has not been studied in T cell biology. Single-cell RNA-seq analyses demonstrated male-biased Zfp148 expression and regulatory activity in PE CD8+ T cells stimulated by AR. T cell receptor (TCR) engagement and chronic exhaustion induced Zfp148 expression in CD8+ T cells, and its deletion led to better effector function in vitro. The in vivo persistence of Zfp148 null T cells was compromised. Hypothesis. AR-regulated ZFP148 can suppress CD8+ T cell effector function and contributes to male-biased BC. Aim 3: Investigate the role of AR and epigenetic modifiers in CD8+ T cell exhaustion and tumor response to immunotherapy. The impact of sex chromosome-encoded epigenetic modifiers in BC – including KDM5D, UTY, and KDM6A – on immunity especially in the CD8+ compartment is a major gap in the field. In collaboration with Project 2, we found that loss of the Y chromosome (LOY) (especially the genes Kdm5d and Uty) contributes to CD8+ T cell exhaustion in BC. Hypothesis. Sex hormones and sex chromosome-encoded epigenetic modifiers contribute to CD8+ T cell exhaustion and BC sensitivity to ICB.

项目 1 – 摘要性别是一个未被充分研究的生物变量，对免疫功能有重大影响，包括在这种情况下癌症。然而，在非癌症中发现的性别偏见背后的免疫学机制生殖器官，例如膀胱癌（BC），仍然难以捉摸。 BC 发病率的男性偏见在对其他已知风险因素的调整表明了这种性别二态性的基本生物学基础。目的：明确雄激素、AR 靶基因和性染色体影响的分子机制。编码的表观遗传修饰因子导致肿瘤中 CD8+ T 细胞耗竭的性别差异微环境（TME）。影响：我们的研究将揭示免疫学基础和机制 CD8+ T 细胞耗竭导致 BC 的性别偏见，这对改善所有人的 ICB 方法具有影响癌症通过三个具体目标。目标 1：确定 AR-TCF1 和 AR-TOX 在 CD8+ T 细胞耗竭中的作用和肿瘤控制。雄激素影响 T 细胞并导致癌症的分子机制进展尚不清楚。男性 CD8+ 肿瘤浸润淋巴细胞 (TIL) 优先采用 TCF1+ PE 状态由于 AR 直接激活 Tcf7。假设。雄激素信号建立稳定的 TCF1 驱动 CD8+ T 细胞中的转录网络通过 TOX 的调节而有利于耗竭，TOX 是另一个关键因素促进 T 细胞耗竭的转录因子 (TF)。目标 2：确定 AR-ZFP148 在 T 细胞中的作用效应器分化。 TF ZFP148 调节非免疫细胞类型的细胞增殖和存活，但具有尚未在 T 细胞生物学中进行研究。单细胞 RNA-seq 分析证明 Zfp148 表达偏向男性 AR 刺激的 PE CD8+ T 细胞的调节活性。 T 细胞受体 (TCR) 参与和慢性疲劳诱导 CD8+ T 细胞中 Zfp148 表达，其缺失导致体外效应功能更好。这 Zfp148 null T 细胞的体内持久性受到损害。假设。 AR调节的ZFP148可以抑制 CD8+ T 细胞效应器功能并有助于男性偏向 BC。目标 3：研究 AR 和 AR 的作用 CD8+ T 细胞耗竭和肿瘤对免疫治疗反应的表观遗传修饰剂。性的影响 BC 中染色体编码的表观遗传修饰因子（包括 KDM5D、UTY 和 KDM6A）对免疫的影响尤其是在CD8+隔室领域是一大空白。与项目 2 合作，我们发现损失 Y 染色体 (LOY) 的缺失（尤其是 Kdm5d 和 Uty 基因）导致 BC 中 CD8+ T 细胞耗竭。假设。性激素和性染色体编码的表观遗传修饰剂有助于 CD8+ T 细胞疲劳和 BC 对 ICB 的敏感性。