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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.

项目概要/摘要尽管免疫系统完整，肿瘤生长和转移仍被认为是贫困的主要证据肿瘤细胞的免疫原性，但增加抗肿瘤反应的免疫疗法的尝试在很大程度上是不成功。肿瘤免疫治疗的一个主要障碍是调节性 T 介导的免疫抑制 (Treg) 细胞，通过抑制效应 T (Teff) 的功能来调节免疫系统细胞。然而，目前针对 Treg 的方法仅具有短暂的功效并且高度不具有特异性。开发控制 Treg 功能的新方法对于改善肿瘤免疫治疗至关重要，并且该项目的中心目标。 Treg 抑制功能由转录因子 Forkhehgead 介导 P3 框（FoxP3）。我们的初步数据表明，泛素特异性肽酶 22 (USP22) 是 FoxP3 表达，表明 USP22 在 Treg 抑制功能和稳定性中发挥关键作用。更多的重要的是，T 细胞中的 USP22 基因抑制很大程度上削弱了 Treg 的抑制功能不损害甚至增强常规 CD4 和 CD8 T 细胞激活的免疫反应，表明USP22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 USP22Treg-KO 小鼠中 EG7 淋巴瘤和 B16 黑色素瘤的抗肿瘤反应增强。基于这些初步观察，我们假设 USP22 是 Treg 抑制的新型调节因子通过调节 FoxP3 表达发挥作用，是增强抗肿瘤作用的潜在治疗靶点免疫。这一假设将通过三个目标来解决。目标 1 将重点研究 USP22 在维持Treg抑制功能。目标 2 将确定具体的分子机制 USP22 介导 FoxP3 表达。目标 3 将评估 USP22 抑制的临床前疗效使用异种移植和自发黑色素瘤模型进行抗肿瘤免疫。研究将提供对 Treg 生物学和调控的基本见解，以及 USP22 靶向抗肿瘤免疫的基本原理治疗。