Regulatory T cells in cancer therapy

调节性 T 细胞在癌症治疗中的应用

基本信息

批准号：
10209436
负责人：
WEIPING ZOU
金额：
$ 64.73万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209436
关键词：
Address Adenosine Affect Antigen-Presenting Cells Apoptosis Apoptotic Behavior Biological Biology Cancer Patient Cell Communication Cell physiology Cells Clinical Clinical Research Colon Carcinoma Data Dendritic Cells Development Disease model Exhibits FOXP3 gene Family Glucose Glycolysis Homeostasis Human Immune Immune response Immunity Immunosuppression Immunotherapy Impairment Ligands MC38 Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mediating Memory Metabolic Metabolic Pathway Metabolism Modeling Molecular Monoclonal Antibodies Mus Myelogenous Myeloid Cells Nature Necrosis Nutrient Oxidative Stress Oxygen PD-L1 blockade Pathway interactions Phagocytosis Phenotype Procollagen-Proline Dioxygenase Production Proteins Regulation Regulatory T-Lymphocyte Reporting Signal Transduction Surface T memory cell T-Cell Activation T-Lymphocyte Technology Testing Translational Research Treatment Efficacy Tumor Antigens Tumor Immunity Vaccination Warburg Effect Work Zinc antigen-specific T cells base cancer immunotherapy cancer therapy cancer type checkpoint therapy clinical predictors design effector T cell empowered immunogenicity improved melanoma novel oxidized lipid potassium ion practical application programmed cell death ligand 1 receptor recruit response stem success trafficking tumor tumor immunology tumor metabolism tumor microenvironment

项目摘要

Project Summary Extensive studies have been conducted to define the development, conversion, stability, and regulatory mechanisms of CD4+Foxp3+ regulatory T cells (Tregs) in homeostasis and a variety of disease models. It is well-known that Tregs are recruited, converted, and expanded in the tumor microenvironment and act as one of the major immunosuppressive mechanisms dampening spontaneous tumor-associated antigen (TAA)- specific T cell immunity and immunotherapy and active vaccination induced anti-tumor immunity. However, how Tregs behave in the metabolically abnormal tumor microenvironment remains unknown. The Warburg effect is an important metabolic feature in many types of cancer. Given that nutrients including glucose are poorly replenished in the tumor, it is assumed that T cell glycolytic metabolism has been altered due to the Warburg effect in the tumor microenvironment. In support of this, poor glycolysis can alter effector memory T cell function in the tumor microenvironment. In addition, the oxygen-sensing prolyl-hydroxylase proteins, necrotic cells released potassium ions, and abnormal zinc metabolism can impair effector T cell function in the tumor microenvironment. These studies underscore the significance of metabolic regulation of memory T cells in the tumor. Tregs exhibit a memory and effector phenotype in the human tumor microenvironment. It is unknown whether Tregs are subject to glycolytic regulation in the tumor. Furthermore, oxidative stress is an additional metabolic feature in the tumor microenvironment. Myeloid dendritic cells (DCs) are phenotypically and functionally altered by oxidative stress in the tumor microenvironment. However, it is unknown whether oxidative stress alters Treg phenotype and function in the tumor and affects cancer immunotherapy. To address these questions, we have examined the phenotypic and functional nature of Tregs in human ovarian cancer and several types of mouse cancer. We have found that Tregs are highly apoptotic in the tumor microenvironment. Interestingly, apoptotic Tregs are superior suppressors via a distinct mechanism. Furthermore, oxidative stress, rather than glycolysis, is a metabolic mechanism controlling tumor Treg functional behavior and tempering therapeutic efficacy of immune checkpoint therapy. This project is to conduct comprehensive molecular, functional, translational, and clinical research on the nature of Tregs and their metabolic pathway in the cancer microenvironment. We will provide rich opportunities to take our understanding of Treg biology in the tumor to a new level of basic and practical application. Our specific aims are: Aim 1 is to test our hypothesis that oxidative stress controls Treg apoptosis in the tumor microenvironment. Aim 2 is to determine the molecular mechanisms controlling the energy circuit of Tregs and the interaction between Tregs and APCs in tumor.

项目概要已经进行了广泛的研究来定义开发、转换、稳定性和监管 CD4+Foxp3+调节性T细胞（Treg）在稳态和多种疾病模型中的机制。这是众所周知，Tregs 在肿瘤微环境中被招募、转化和扩增，并作为一个整体发挥作用。抑制自发性肿瘤相关抗原（TAA）的主要免疫抑制机制- 特异性T细胞免疫和免疫治疗以及主动疫苗接种诱导的抗肿瘤免疫。然而，如何 Tregs 在代谢异常的肿瘤微环境中的行为仍不清楚。瓦尔堡效应是许多类型癌症的重要代谢特征。鉴于营养素包括肿瘤中葡萄糖补充不良，推测 T 细胞糖酵解代谢已改变由于肿瘤微环境中的 Warburg 效应。支持这一点的是，糖酵解不良可以改变效应器记忆T细胞在肿瘤微环境中的功能。此外，氧敏感脯氨酰羟化酶蛋白质、坏死细胞释放钾离子以及锌代谢异常会损害效应T细胞在肿瘤微环境中发挥作用。这些研究强调了代谢调节的重要性肿瘤中的记忆T细胞。 Tregs 在人类肿瘤微环境中表现出记忆和效应表型。尚不清楚是否 Tregs 在肿瘤中受到糖酵解调节。此外，氧化应激是一种额外的代谢肿瘤微环境的特征。骨髓树突状细胞 (DC) 表型和功能发生改变肿瘤微环境中的氧化应激。然而，目前尚不清楚氧化应激是否会改变 Treg 肿瘤的表型和功能并影响癌症免疫治疗。为了解决这些问题，我们有检查了人类卵巢癌和几种小鼠卵巢癌中 Tregs 的表型和功能性质癌症。我们发现Tregs在肿瘤微环境中高度凋亡。有趣的是，细胞凋亡 Tregs 通过独特的机制成为卓越的抑制因子。此外，氧化应激而不是糖酵解，是一种控制肿瘤 Treg 功能行为并调节治疗功效的代谢机制免疫检查点疗法。该项目旨在进行全面的分子、功能、翻译和癌症微环境中Tregs的性质及其代谢途径的临床研究。我们将提供了丰富的机会，将我们对肿瘤中 Treg 生物学的理解提升到基础和新水平实际应用。我们的具体目标是：目标 1 是检验我们的假设，即氧化应激控制肿瘤中的 Treg 细胞凋亡微环境。目标 2 是确定控制能量回路的分子机制肿瘤中Tregs的作用以及Tregs和APC之间的相互作用。