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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的众所周知，肿瘤微环境内的免疫抑制生态市场（TME）肿瘤免疫逃生和进展，其中调节性T细胞（Tregs）发挥重要作用。尽管在识别转录和 TME中Treg功能调节的表观遗传事件，我们的基本差距仍然存在于我们的了解介导Treg生存，扩张和的详细表观遗传网络 TME诱导的免疫抑制功能增强。液泡蛋白排序72同源物（VPS72），一种组蛋白伴侣，可识别和交换组蛋白H2A.Z标准组蛋白 H2a在体外研究中已显示，这些研究调节了基因转录，特别是相关的基因转录线粒体代谢通过染色质重塑，尽管体内生物学功能 VPS72仍然未知。我们的初步研究揭示了较高的表达和阳性 TME内部的Tregs中VPS72和FOXP3之间的相关性。有趣的是，我们的Treg特异性 VPS72 KO和H2A.Z KO小鼠模型显示出正常的胸腺Treg发育，但急剧中断的外围Treg维护和功能。这些结果导致了我们中心假设是VPS72是TME因子可以诱导的关键表观遗传因素并通过TME中Treg的H2A.Z染色质重塑来增强Treg的稳定性和功能。在拟议的研究中，我们使用Treg特异性本构和诱导基因缺失小鼠模型确定VPS72和H2AZ在周围Treg细胞维持中的作用，癌症的稳定性和功能。使用Scrna-Seq，Scatac-Seq和Cut＆Run-合并 SEQ多摩变分析，我们将描述表观遗传策略和详细的分子机理和信号通路VPS72用于控制Treg稳态和功能。在移植和自发的黑色素瘤肿瘤模型中，我们将评估抗肿瘤作用 VPS72和H2AZ抑制。此外，TME因子和相关分子机制在上调VPS72在TME中Tregs的表达时也将进行研究。结果拟议的研究不仅将增强我们对Treg生物学的理解，还将促进开发更有效的基于TREG的癌症治疗策略。