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
- 来源:
- 关键词:AddressAffectAntitumor ResponseApoptosisAutoimmune ResponsesBiologyCD8-Positive T-LymphocytesCellsCessation of lifeChronicClinicalDataDendritic CellsDeubiquitinationDevelopmentEnzymesFOXP3 geneGeneticGenetic TranscriptionGoalsGrowthHomeostasisHumanImmune responseImmune systemImmunityImmunosuppressionImmunotherapyImpairmentIn VitroKnockout MiceKnowledgeLymphomaMalignant NeoplasmsMediatingModelingMolecularMusNeoplasm MetastasisOncogenesPatientsPeptide HydrolasesPharmacologyPopulationPrognosisProteinsRegulationRegulatory T-LymphocyteRoleSkin CancerT-Cell ActivationT-LymphocyteTestingTumor ImmunityUbiquitinUbiquitinationVaccinationXenograft procedureagedanti-tumor immune responsebasecancer cellcancer typecell growtheffector T cellefficacy evaluationforkhead proteingenetic signatureimmunogenicityimprovedinhibitorinsightmelanomaneoplasm immunotherapyneoplastic cellnovelpreclinical efficacytherapeutic targettranscription factortumortumor growthtumor 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。
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:
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Clinical analysis and therapeutic development of exosomal ACE2
外泌体ACE2的临床分析和治疗进展
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Clinical analysis and therapeutic development of exosomal ACE2
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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
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10152123 - 财政年份:2021
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$ 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
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10545001 - 财政年份:2021
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A deubiquitination module controls Treg adaptation to tumor microenvironment
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10320965 - 财政年份:2021
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