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:
  • 金额:
    $ 34.51万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Endoplasmic reticulum-associated degradation and beyond: The multitasking roles for HRD1 in immune regulation and autoimmunity.
  • DOI:
    10.1016/j.jaut.2020.102423
  • 发表时间:
    2020-05
  • 期刊:
  • 影响因子:
    12.8
  • 作者:
    Xu, Yuanming;Fang, Deyu
  • 通讯作者:
    Fang, Deyu
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Deyu Fang其他文献

Deyu Fang的其他文献

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{{ truncateString('Deyu Fang', 18)}}的其他基金

VPS72 controls Treg cell stability and adaptation to tumor microenvironment
VPS72 控制 Treg 细胞稳定性和对肿瘤微环境的适应
  • 批准号:
    10754017
  • 财政年份:
    2023
  • 资助金额:
    $ 34.51万
  • 项目类别:
Clinical analysis and therapeutic development of exosomal ACE2
外泌体ACE2的临床分析和治疗进展
  • 批准号:
    10531071
  • 财政年份:
    2022
  • 资助金额:
    $ 34.51万
  • 项目类别:
Clinical analysis and therapeutic development of exosomal ACE2
外泌体ACE2的临床分析和治疗进展
  • 批准号:
    10666589
  • 财政年份:
    2022
  • 资助金额:
    $ 34.51万
  • 项目类别:
A deubiquitination module controls Treg adaptation to tumor microenvironment
去泛素化模块控制 Treg 对肿瘤微环境的适应
  • 批准号:
    10152123
  • 财政年份:
    2021
  • 资助金额:
    $ 34.51万
  • 项目类别:
A deubiquitination module controls Treg adaptation to tumor microenvironment
去泛素化模块控制 Treg 对肿瘤微环境的适应
  • 批准号:
    10545001
  • 财政年份:
    2021
  • 资助金额:
    $ 34.51万
  • 项目类别:
Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation
ERα相关降解对节律性 m6A RNA 修饰的调节
  • 批准号:
    10297978
  • 财政年份:
    2021
  • 资助金额:
    $ 34.51万
  • 项目类别:
Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation
ERα相关降解对节律性 m6A RNA 修饰的调节
  • 批准号:
    10615181
  • 财政年份:
    2021
  • 资助金额:
    $ 34.51万
  • 项目类别:
A deubiquitination module controls Treg adaptation to tumor microenvironment
去泛素化模块控制 Treg 对肿瘤微环境的适应
  • 批准号:
    10320965
  • 财政年份:
    2021
  • 资助金额:
    $ 34.51万
  • 项目类别:
Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation
ERα相关降解对节律性 m6A RNA 修饰的调节
  • 批准号:
    10454294
  • 财政年份:
    2021
  • 资助金额:
    $ 34.51万
  • 项目类别:
Novel Role of Hepatic SEL1L-HRD1 ERAD in FGF21 Gene Transcription
肝脏 SEL1L-HRD1 ERAD 在 FGF21 基因转录中的新作用
  • 批准号:
    9792378
  • 财政年份:
    2018
  • 资助金额:
    $ 34.51万
  • 项目类别:

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