Interleukin-35 and the tumor microenvironment

Interleukin-35 与肿瘤微环境

基本信息

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
项目类别：
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

项目摘要

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内的抑制性机制代表有效抗肿瘤的主要障碍免疫。尽管在抑制性的临床踪迹中已经报道了多种肿瘤类型的惊人效率接收器封锁，很明显，需要将其他抑制作用机制定为实质性改善大多数肿瘤类型的治疗结果。调节性T细胞（Tregs）是抗肿瘤的潜在抑制剂免疫。尽管有针对性的Treg消融导致多种人类癌模型中的肿瘤快速收缩，但由于随后的严重自身免疫性和炎症，这不是可行的治疗方法结果。在肿瘤微环境中选择性地限制Treg活性的更多针对性方法虽然Tregs使用了多个控制T细胞功能的抑制性机制，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标。 Interleukin-35（IL35），EBI3/IL12A异二聚体，是一个 TREG产生的抑制性细胞因子是T细胞增殖和功能的潜在抑制剂。 Treg衍生 IL35还可以促进通过IL35抑制的诱导调节性T细胞群的发展（ITR35），这反过来又会有助于抑制肿瘤内环境。但是，身体影响 IL35在肿瘤微环境中的作用机理和作用机理在很大程度上尚不清楚。在这种竞争中更新应用，我们将确定IL35如何调节肿瘤微环境。目标1：在肿瘤微环境中解剖IL35+ Treg的功能和命运。使用EBI3记者，有条件的和线条追踪小鼠，我们将确定Tregs生产IL35的物理重要性在肿瘤以及EBI3+与EBI3 – Tregs的作用和命运中。目标2：确定IL35对肿瘤微环境中CD8+ T细胞的影响。使用EBI3 有条件的小鼠，我们将确定Treg衍生的IL35对CD8+ T细胞功能和命运的影响肿瘤。该项目将对我们对身体重要性的理解产生重大影响， IL35在肿瘤微环境中的作用机理。考虑到我们发现了IL35并有许多独特的工具来探究其功能，我们处于进行这项研究的最佳位置。