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

• 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
• 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

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 性别是一个研究不足的生物变量，对免疫功能有重大影响，包括在 癌症的威胁。然而，在癌症患者中发现的性别偏见背后的免疫学机制 生殖器官，如膀胱癌(BC)，仍然难以捉摸。男性在BC发病率方面的偏见在以下情况下持续存在 对其他已知风险因素的调整表明了这种性别二型性的基本生物学基础。 目的：明确雄激素、AR靶基因和性染色体的分子机制。 编码的表观遗传修饰物在肿瘤中CD8+T细胞耗竭方面的性别差异 微环境(TME)。影响：我们的研究将揭示一种免疫学基础和机制 CD8+T细胞耗竭有助于BC患者的性别偏见，并对改善ICB方法对ALL的影响 癌症通过三个具体的目标。目的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 进展情况尚不清楚。男性CD8+肿瘤浸润性淋巴细胞优先进入TCF1+PE状态 这是由于AR直接激活了TCF7。假设。雄激素信号转导建立稳定的TCF1驱动 CD8+T细胞中的转录网络通过TOX的调节有利于衰竭，TOX是另一个关键的 促进T细胞耗竭的转录因子(TF)。目的2：确定AR-ZFP148在T细胞中的作用 效应器分化。TFZFP148调节非免疫细胞类型的细胞增殖和存活，但具有 在T细胞生物学中没有被研究过。单细胞RNA-seq分析显示Zfp148表达偏向于男性 AR刺激的PE CD8+T细胞的调节活性。T细胞受体(TCR)参与与慢性 力竭可诱导CD8+T细胞表达Zfp148，Zfp148缺失在体外具有较好的效应功能。这个 Zfp148缺失T细胞在体内的持久性受到影响。假设。AR调节的ZFP148可以抑制 CD8+T细胞效应器的功能，并参与了男性偏见的BC。目的3：研究AR和AR的作用 表观遗传调节剂在CD8+T细胞耗竭和肿瘤免疫治疗反应中的作用。性的影响 BC中染色体编码的表观遗传修饰物--包括KDM5D、UTY和KDM6A--对免疫的影响 尤其是在CD8+亚群中是该领域的一大空白。在与项目2的合作中，我们发现了这种损失 Y染色体(LOY)的缺失(尤其是Kdm5d和UTY基因)与BC的CD8+T细胞耗竭有关。 假设。性激素和性染色体编码的表观遗传修饰物对CD8+T细胞的作用 精疲力竭与BC对ICB的敏感性。