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.

项目摘要 肿瘤微环境中的抑制机制是有效抗肿瘤的主要障碍。 免疫力尽管在临床试验中已经报道了在多种肿瘤类型中具有显著的功效，但是抑制性的抗肿瘤药物在临床试验中已经报道了在多种肿瘤类型中具有显著的功效。 受体阻滞剂，很明显，额外的抑制机制将需要有针对性的实质上 改善大多数肿瘤类型治疗效果。调节性T细胞（Regulatory T cells，TCFs）是一种有效的抗肿瘤抑制剂 免疫力尽管靶向Treg消融在多种人类癌症模型中导致肿瘤快速缩小， 这不是一种可行的治疗方法， 后果因此，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 沿着深入了解其作用机制。虽然Tencent使用多个 尽管存在控制T细胞功能的抑制机制，但尚不清楚哪些在肿瘤微环境中占主导地位 因此可能是癌症中可行的治疗靶点。白细胞介素-35（IL-35），一种Ebi 3/IL-112 α异源二聚体，是一种免疫调节剂。 T细胞增殖和功能的有效抑制因子。Treg衍生 IL 35还可以促进诱导的调节性T细胞群的发展，该调节性T细胞群通过IL 35抑制免疫应答。 （iTr35），这反过来可以有助于抑制性肿瘤内环境。然而，生理影响 IL 35在肿瘤微环境中的作用机制在很大程度上是未知的。在这个竞争激烈的 更新申请，我们将确定IL 35如何调节肿瘤微环境。 目的1：探讨IL 35 + T细胞在肿瘤微环境中的作用和转归。使用Ebi3报告器， 条件和谱系追踪小鼠，我们将确定TCFs产生IL 35的生理重要性， 在肿瘤中的作用以及Ebi3+与Ebi3-TcB的作用和命运。 目的2：确定IL 35对肿瘤微环境中的CD8 + T细胞的影响。使用Ebi3 在条件小鼠中，我们将确定Treg衍生的IL 35对CD8 + T细胞的功能和命运的影响。 肿瘤的 这个项目将对我们理解生理学的重要性产生重大影响， IL 35在肿瘤微环境中的作用机制。鉴于我们发现了IL35， 有许多独特的工具来探索它的功能，我们处于进行这项研究的最佳位置。