VPS72 controls Treg cell stability and adaptation to tumor microenvironment

VPS72 控制 Treg 细胞稳定性和对肿瘤微环境的适应

• 批准号: 10754017
• 负责人: Deyu Fang
• 金额: $ 65.81万
• 依托单位: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754017
• 关键词: ATAC-seq; Age; Amino Acids; Autoimmune Diseases; Biological Process; Biology; Cell Lineage; Cell Maintenance; Cell Survival; Cell physiology; Cells; Cellular biology; Chromatin; Chromatin Structure; Development; Epigenetic Process; Event; FOXP3 gene; Gene Deletion; Genetic Transcription; Glucose; Histone H2A; Histones; Homeostasis; Homologous Gene; Hypoxia; Immune; Immunosuppression; Immunotherapy; In Vitro; Individual; Infiltration; Interruption; Intervention; Knock-out; Knockout Mice; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Chaperones; Mus; Oncogenes; Organ; Pathway interactions; Peripheral; Phenocopy; Play; Procedures; Protein Isoforms; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Pathway; Stress; T-Cell Development; Testing; Thymus Gland; Transplantation; Tumor Escape; Tumor Immunity; Tumor Promotion; Vacuolar Protein Sorting; Variant; Work; anti-PD-1; antitumor effect; cancer immunotherapy; cancer therapy; chromatin remodeling; cytokine; epigenetic regulation; experience; fitness; forkhead protein; immune checkpoint blockade; immune function; immunoregulation; improved; in vivo; insight; melanoma; mitochondrial metabolism; mouse model; multiple omics; neoplastic cell; overexpression; single-cell RNA sequencing; success; synergism; transcriptome sequencing; tumor; tumor immunology; tumor microenvironment

Abstract It became well known that the immune suppressive niche inside the tumor microenvironment (TME) accounts for tumor immune escape and progression, in which the regulatory T cells (Tregs) play an important role. Although some progress has been made in identifying transcriptional and epigenetic events in Treg functional regulation in TME, a fundamental gap remains in our understanding the detailed epigenetic networks mediating Treg survival, expansion and enhanced immune suppressive function induced by TME. Vacuolar protein sorting 72 homolog (VPS72), a histone chaperone that recognizes and exchanges histone H2A.Z for standard histone H2A, has been shown in in vitro studies that regulate gene transcriptions especially related in mitochondrial metabolism through chromatin remodeling, although the in vivo biological function of VPS72 remains unknown. Our preliminary studies revealed the higher expression and positive correlation between VPS72 and Foxp3 in the Tregs inside the TME. Intriguingly, our Treg-specific VPS72 KO and H2A.Z KO mouse models showed normal thymic Treg development, but dramatically interrupted peripheral Treg maintenance and function. These results led to our central hypothesis that VPS72 is a critical epigenetic factor that can be induced by TME factors and enhance Treg stability and function through H2A.Z chromatin remodeling of Treg in the TME. In the proposed studies, we are using Treg-specific constitutive and inducible gene deletion mouse models to determine the role of VPS72 and H2AZ in peripheral Treg cell maintenance, stability and function in the cancer. Using combined scRNA-seq, scATAC-seq, and CUT & RUN- seq multi-omic analysis, we will delineate the epigenetic strategies and detailed molecular mechanisms and signaling pathways VPS72 used in controlling Treg homeostasis and function. In transplant and spontaneous melanoma tumor models, we will evaluate the anti-tumor effects of VPS72 and H2AZ suppression. Furthermore, TME factors and related molecular mechanisms in upregulating VPS72 expression of Tregs in TME will be also investigated. Results from the proposed study will not only enhance our understanding of Treg biology but will also facilitate the development of more efficient Treg-based intervention strategies for cancer treatment.

摘要 众所周知，肿瘤微环境内的免疫抑制生态位 (TME)解释了肿瘤免疫逃逸和进展，其中调节性T细胞（TCFs） 发挥重要作用。虽然在鉴定转录和转录水平上已经取得了一些进展， TME中Treg功能调节的表观遗传事件，我们的研究中仍然存在一个根本性的空白。 了解详细的表观遗传网络介导Treg存活，扩张和 增强TME诱导的免疫抑制功能。蛋白质分选72同源物 （VPS 72），一种识别组蛋白H2A.Z并将其交换为标准组蛋白的组蛋白伴侣 体外研究表明H2 A可以调节基因转录，尤其是与 线粒体代谢通过染色质重塑，虽然在体内的生物功能， VPS 72仍然未知。我们的初步研究表明，高表达和阳性 VPS 72和Foxp 3在TME内的T细胞中的相关性。有趣的是，我们的Treg特异性 VPS 72 KO和H2A.Z KO小鼠模型显示正常的胸腺Treg发育，但 严重干扰了外周Treg的维持和功能。这些结果导致我们 中心假设VPS 72是一个关键的表观遗传因子，可由TME因子诱导 并通过TME中Treg的H2A.Z染色质重塑增强Treg稳定性和功能。 在拟议的研究中，我们使用Treg特异性组成型和诱导型基因缺失， 小鼠模型以确定VPS 72和H2 AZ在外周Treg细胞维持中的作用， 稳定性和功能。使用组合的scRNA-seq、scATAC-seq和CUT & RUN- seq多组学分析，我们将描绘表观遗传策略和详细的分子生物学特征。 VPS 72用于控制Treg稳态和功能的机制和信号传导途径。 在移植和自发性黑色素瘤模型中，我们将评估抗肿瘤作用 VPS 72和H2 AZ抑制。此外，TME因素和相关分子机制 还将研究TME中TdR的VPS 72表达的上调。结果 拟议的研究不仅将增强我们对Treg生物学的理解， 开发更有效的基于Treg的癌症治疗干预策略。