Interleukin-35 and the tumor microenvironment

Interleukin-35 与肿瘤微环境

• 批准号: 9306799
• 负责人: Dario AA Vignali
• 金额: $ 38.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306799
• 关键词: Ablation; Address; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cell Count; Cell Proliferation; Cell physiology; Clinical; Development; Disease; Employee Strikes; Event; Future; Genetic; Genetic Transcription; Homeostasis; Human; Immune; Immunity; In Vitro; Inflammatory; Interleukins; Knock-in; Knock-out; Link; Longevity; Maintenance; Malignant Neoplasms; Modeling; Mus; Mutant Strains Mice; Peptides; Phenotype; Physiological; Population; Positioning Attribute; Production; Protein p53; Regulatory T-Lymphocyte; Reporter; Reporting; Research; Role; Suppressor-Effector T-Lymphocytes; System; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Transgenic Organisms; Tumor Immunity; cancer therapy; cytokine; exhaustion; experimental study; improved; inhibitor/antagonist; novel; prevent; prophylactic; receptor; receptor expression; therapeutic target; therapy outcome; tool; treatment strategy; tumor; tumor growth; tumor microenvironment

PROJECT SUMMARY Inhibitory mechanisms within the tumor microenvironment represent major barriers to effective antitumor immunity. Although striking efficacy in a variety of tumor types has been reported in clinical trails with inhibitory receptor blockade, it's clear that additional inhibitory mechanisms will need to be targeted to substantially improve therapeutic outcome in most tumor types. Regulatory T cells (Tregs) are potent inhibitors of anti-tumor immunity. Although targeted Treg ablation results in rapid tumor shrinkage in multiple models of human cancer, this is not a viable therapeutic approach due to the subsequent severe autoimmune and inflammatory consequences. Thus more targeted approaches to limit Treg activity selectively in the tumor microenvironment are needed, along with in depth understanding of their mechanism of action. Although Tregs use multiple inhibitory mechanisms to control T cell function, it is unclear which are dominant in the tumor microenvironment and thus may be viable therapeutic targets in cancer. Interleukin-35 (IL35), an Ebi3/Il12a heterodimer, is an inhibitory cytokine produced by Tregs that is a potent suppressor of T cell proliferation and function. Treg-derived IL35 can also promote the development of an induced regulatory T cell population that suppresses via IL35 (iTr35), which in turn can contribute to the suppressive intratumoral milieu. However, the physiological impact and mechanism of action of IL35 within the tumor microenvironment are largely unknown. In this competitive renewal application, we will determine how IL35 modulates the tumor microenvironment. AIM 1: Dissecting the function and fate of IL35+ Tregs in the tumor microenvironment. Using Ebi3 reporter, conditional and linage tracing mice, we will determine the physiological importance of IL35 production by Tregs in tumors and the role and fate of Ebi3+ versus Ebi3– Tregs. AIM 2: Determining the impact of IL35 on CD8+ T cells within the tumor microenvironment. Using Ebi3 conditional mice, we will determine the impact of Treg-derived IL35 on the function and fate of CD8+ T cells in tumors. This project will have a significant impact of our understanding of the physiological importance and mechanism of action of IL35 in the tumor microenvironment. Given that we discovered IL35 and have many unique tools to probe its function, we are in the best position to conduct this research.

项目概要 肿瘤微环境内的抑制机制是有效抗肿瘤的主要障碍 免疫。尽管在临床试验中已报道了对多种肿瘤类型的显着疗效，但具有抑制作用 受体阻断，很明显，需要有针对性地采取额外的抑制机制 改善大多数肿瘤类型的治疗效果。调节性 T 细胞 (Treg) 是抗肿瘤的有效抑制剂 免疫。尽管靶向 Treg 消融可导致多种人类癌症模型中的肿瘤快速缩小， 由于随后出现严重的自身免疫和炎症，这不是一种可行的治疗方法 结果。因此，更有针对性的方法可以选择性地限制肿瘤微环境中的 Treg 活性 需要深入了解其作用机制。尽管 Tregs 使用多个 控制 T 细胞功能的抑制机制，目前尚不清楚哪些机制在肿瘤微环境中占主导地位 因此可能是癌症的可行治疗靶点。 Interleukin-35 (IL35) 是一种 Ebi3/Il12a 异二聚体，是一种 由 Tregs 产生的抑制性细胞因子，是 T 细胞增殖和功能的有效抑制剂。 Treg衍生的 IL35 还可以促进诱导性调节性 T 细胞群的发育，通过 IL35 抑制 (iTr35)，这反过来又有助于抑制瘤内环境。但生理上的影响 IL35 在肿瘤微环境中的作用机制在很大程度上尚不清楚。在这场竞争激烈的 更新申请后，我们将确定IL35如何调节肿瘤微环境。 目标 1：剖析肿瘤微环境中 IL35+ Tregs 的功能和命运。使用Ebi3记者， 条件和谱系追踪小鼠，我们将确定 Tregs 产生 IL35 的生理重要性 在肿瘤中以及 Ebi3+ 与 Ebi3- Tregs 的作用和命运。 目标 2：确定 IL35 对肿瘤微环境中 CD8+ T 细胞的影响。使用Ebi3 条件小鼠，我们将确定 Treg 衍生的 IL35 对 CD8+ T 细胞的功能和命运的影响 肿瘤。 该项目将对我们对生理重要性的理解产生重大影响， IL35在肿瘤微环境中的作用机制。鉴于我们发现了 IL35 并且已经 许多独特的工具来探索其功能，我们最有能力进行这项研究。