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Targeting a Treg deubiquitinase in antitumor immune therapy

抗肿瘤免疫治疗中针对 Treg 去泛素酶的研究

基本信息

批准号：
10429984
负责人：
Deyu Fang
金额：
$ 34.51万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10429984
关键词：
Address Affect Antitumor Response Apoptosis Autoimmune Responses Biology CD8-Positive T-Lymphocytes Cells Cessation of life Chronic Clinical Data Dendritic Cells Deubiquitination Development Enzymes FOXP3 gene Genetic Genetic Transcription Goals Growth Homeostasis Human Immune response Immune system Immunity Immunosuppression Immunotherapy Impairment In Vitro Knockout Mice Knowledge Lymphoma Malignant Neoplasms Mediating Modeling Molecular Mus Neoplasm Metastasis Oncogenes Patients Peptide Hydrolases Pharmacology Population Prognosis Proteins Regulation Regulatory T-Lymphocyte Role Skin Cancer T-Cell Activation T-Lymphocyte Testing Tumor Immunity Ubiquitin Ubiquitination Vaccination Xenograft procedure aged anti-tumor immune response base cancer cell cancer type cell growth effector T cell efficacy evaluation forkhead protein genetic signature immunogenicity improved inhibitor insight melanoma neoplasm immunotherapy neoplastic cell novel preclinical efficacy therapeutic target transcription factor tumor tumor growth tumor progression

项目摘要

Project Summary/Abstract Tumor growth and metastasis, despite an intact immune system, were considered prime evidence of the poor immunogenicity of tumor cells, but attempts at immunotherapy to increase anti-tumor responses were largely unsuccessful. A major hurdle in tumor immunotherapy is the immunosuppression mediated by Regulatory T (Treg) cells, which function to modulate the immune system by suppressing the function of effector T (Teff) cells. However, current approaches in targeting Treg have only transient efficacy and are highly unspecific. The development of new ways to control Treg functions is essential to improving tumor immunotherapy, and is a central goal of this project. Treg suppressive function is mediated by the transcription factor Forkhehgead Box P3 (FoxP3). Our preliminary data show that the Ubiquitin-specific peptidase 22 (USP22) is required for FoxP3 expression, suggesting a critical role for USP22 in Treg suppressive function and stability. More importantly, genetic USP22 suppression specifically in T cells largely diminished Treg suppressive functions without impairing, but even enhanced the immune response of conventional CD4 and CD8 T cell activation, indicating that USP22 is an ideal target to specifically inhibit Treg functions to enhance the antitumor immunity. Indeed, challenging of both WT and mice harboring a USP22 genetic deletion in Tregs (USP22Treg-KO) with EG7 lymphoma and B16 melanoma showed an increased in anti-tumor response in USP22Treg-KO mice. Based on these preliminary observations, we hypothesis that USP22 is a novel regulator of Treg suppressive functions through modulating FoxP3 expression and a potential therapeutic target to boost the antitumor immunity. This hypothesis will be addressed in three aims. Aim 1 will focus on studying the role of USP22 on maintaining Treg suppressive function. Aim 2 will determine the specific molecular mechanisms by which USP22 mediates FoxP3 expression. Aim 3 will evaluate the preclinical efficacy of USP22 suppression in antitumor immunity using both xenograft and spontaneous melanoma models. The studies will provide fundamental insights to Treg biology and regulation, and a rationale for USP22 targeting in antitumor immune therapy.

项目总结/摘要尽管免疫系统完好无损，但肿瘤的生长和转移被认为是穷人的主要证据。肿瘤细胞的免疫原性，但免疫治疗，以增加抗肿瘤反应的尝试，在很大程度上，不成功。肿瘤免疫治疗的一个主要障碍是调节性T细胞介导的免疫抑制 Treg）细胞，其通过抑制效应T（Teff）的功能来调节免疫系统。细胞然而，目前靶向Treg的方法仅具有短暂的功效并且是高度非特异性的。控制Treg功能的新方法的开发对于改善肿瘤免疫疗法是必不可少的，这个项目的核心目标。Treg抑制功能由转录因子Forkhehgead介导方框P3（FoxP 3）。我们的初步数据表明，泛素特异性肽酶22（USP 22）是必需的， FoxP 3表达，表明USP 22在Treg抑制功能和稳定性中的关键作用。更重要的是，在T细胞中特异性的遗传性USP 22抑制极大地削弱了Treg抑制功能不损害，甚至增强了常规CD 4和CD 8 T细胞活化的免疫应答，表明USP 22是特异性抑制Treg功能以增强抗肿瘤免疫的理想靶点。事实上，用以下方法挑战WT和Treg 2中携带USP 22基因缺失的小鼠（USP 22 Treg-KO）， EG 7淋巴瘤和B16黑色素瘤在USP 22 Treg-KO小鼠中显示出抗肿瘤应答增加。基于这些初步观察，我们假设USP 22是Treg抑制性调节因子，通过调节FoxP 3表达和潜在的治疗靶点来增强抗肿瘤作用，免疫力这一假设将在三个目标中得到解决。目标1将重点研究USP 22在以下方面的作用：维持Treg抑制功能。目标2将确定特定的分子机制， USP 22介导FoxP 3表达。目的3将评价USP 22抑制在以下患者中的临床前疗效：使用异种移植物和自发性黑素瘤模型的抗肿瘤免疫。这些研究将提供 Treg生物学和调控的基本见解，以及USP 22在抗肿瘤免疫中的靶向原理疗法