Regulatory T cells in cancer therapy

调节性 T 细胞在癌症治疗中的应用

• 批准号: 10361528
• 负责人: WEIPING ZOU
• 金额: $ 63.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10361528
• 关键词: Address; Adenosine; Affect; Antigen-Presenting Cells; Apoptosis; Apoptotic; Behavior; 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

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.

项目摘要 已经进行了广泛的研究，以确定开发，转换，稳定性和监管 CD 4 + Foxp 3+调节性T细胞（TCRs）在稳态和各种疾病模型中的作用机制。是 众所周知，T细胞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接种诱导的抗肿瘤免疫。但如何 肿瘤微环境中代谢异常的肿瘤细胞的行为仍然是未知的。 瓦尔堡效应是许多类型癌症的重要代谢特征。考虑到营养素， 由于肿瘤中葡萄糖的补充不足，因此假定T细胞糖酵解代谢已被改变， 由于肿瘤微环境中的瓦尔堡效应。为了支持这一点，糖酵解不良可以改变效应子。 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和锌代谢异常可损害效应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 在人类肿瘤微环境中，TCLs表现出记忆和效应表型。尚不清楚是否 在肿瘤中，胰蛋白酶受糖酵解调节。此外，氧化应激是一种额外的代谢途径， 肿瘤微环境的特点。髓样树突状细胞（DC）的表型和功能改变 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 肿瘤中的表型和功能，并影响癌症免疫治疗。为了解决这些问题，我们有 在人类卵巢癌和几种类型的小鼠中检查了TcR的表型和功能性质。 癌我们已经发现，在肿瘤微环境中，TGFAP高度凋亡。有趣的是， 通过一种独特的机制，睾酮是上级抑制剂。此外，氧化应激，而不是糖酵解， 是一种控制肿瘤Treg功能行为和调节治疗效果的代谢机制， 免疫检查点疗法该项目是进行全面的分子，功能，翻译， 关于TdR的性质及其在癌症微环境中的代谢途径的临床研究。我们将 提供了丰富的机会，使我们对肿瘤中Treg生物学的理解达到一个新的水平， 实际应用我们的具体目标是： 目的1是验证我们的假设，即氧化应激控制肿瘤中Treg的凋亡 微环境目的2是确定控制能量回路的分子机制 肿瘤组织中T细胞的表达及其与APC的相互作用。