Regulatory T cells in cancer therapy

项目摘要 已经进行了广泛的研究来定义发展、转化、稳定性和调节 CD4+Foxp3+调节性T细胞(Tregs)内稳态及多种疾病模型的机制它是 众所周知，Tregs在肿瘤微环境中被招募、转化和扩展，并作为一个整体发挥作用 抑制自发肿瘤相关抗原(TAA)的主要免疫抑制机制 特异性T细胞免疫及免疫治疗和主动免疫诱导抗肿瘤免疫。然而，如何 Treg在代谢异常的肿瘤微环境中的行为尚不清楚。 华宝效应是许多类型癌症的重要代谢特征。鉴于营养物质包括 肿瘤中葡萄糖补充不足，推测T细胞糖酵解代谢已改变 由于肿瘤微环境中的华宝效应。支持这一点的是，糖酵解不良会改变效应器。 记忆T细胞在肿瘤微环境中的作用。此外，氧敏感的脯氨酸羟基酶 蛋白质、坏死细胞释放钾离子、锌代谢异常可损害效应性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。 Treg在人类肿瘤微环境中表现出记忆和效应表型。目前还不清楚 Treg受制于肿瘤中的糖酵解调节。此外，氧化应激是一种额外的新陈代谢 肿瘤微环境中的特征。髓系树突状细胞(DC)的表型和功能发生改变 通过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 在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 研究了人卵巢癌和几种类型的小鼠中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 Treg通过一种不同的机制是优越的抑制者。此外，氧化应激，而不是糖酵解， 是一种控制肿瘤Treg功能行为和调和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，翻译和 肿瘤微环境中Tregs的性质及其代谢途径的临床研究。我们会 提供丰富的机会，将我们对肿瘤中Treg生物学的了解提升到一个新的基础和水平 实际应用。我们的具体目标是： 目标1是验证我们的假设，即氧化应激控制肿瘤中Treg细胞的凋亡 微环境。目标2是确定控制能量回路的分子机制 Tregs的表达及其与APC在肿瘤中的相互作用。

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.