E3 ligase mediated control of Foxp3 expression and immune suppression-mechanisms and potential as immunotherapeutic target

E3连接酶介导的Foxp3表达和免疫抑制机制的控制以及作为免疫治疗靶点的潜力

基本信息

  • 批准号:
    10331033
  • 负责人:
  • 金额:
    $ 37.91万
  • 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:
    2018-02-01 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Project Summary Tumor cells exploit mechanisms of immune regulation to evade detection and eradication by host defenses. Foxp3+CD4+CD25+ regulatory T cell (Treg)-mediated immune suppression is crucial for immune evasion by tumor cells and an obstacle for successful tumor immunotherapy. Hence, the ability to disrupt Treg function is of major therapeutic significance. Recent work by us and others revealed that the key Treg transcription factor, Foxp3 is subject to polyubiquitination-dependent posttranslational regulation. Particularly, we found the E3 ubiquitin ligase Stub1, which is induced in response to a range of stress signals, facilitates the degradation of Foxp3 providing a potential target for dynamic modulation of Treg suppression. In the current proposal, we are seeking to: 1) Dissect molecular signaling pathways involved in Stub1 expression and its post-translational modification; 2) Understand the consequences of physiological Stub1 induction and genetic deletion for Treg cell homeostasis, differentiation and function; and 3) Test pharmacological activators of Foxp3 ubquitination as novel immunotherapic strategies to undermine immune suppression in the cancer setting. These studies will expand our understanding of the mechanisms behind posttranslational Foxp3 regulation. Specifically, we will further explore pathways determining Stub1 activity and expression, including the previously unappreciated phosphorylation of the ligase by the kinase GS3Kβ. To this end, we will utilize biochemical approaches and well-characterized models of in vitro and in vivo Treg function to establish the consequences of ablating these pathways. Furthermore, pharmacological modifiers of the Stub1/Ubiquitin-dependent pathway for Foxp3 degradation (identified in a drug screen and previous studies) will be tested for efficacy as breakers of immune suppression - a major obstacle for anti-cancer immunotherapy. This vetting will be carried out in an aggressive murine melanoma model (in vivo) as well as in ex vivo studies of human leukocytes obtained from healthy donors and advanced cancer patients. In so doing we will determine the potential therapeutic application of modulating Stub1 activity to boost anti-tumor immunity. Our experiments may reveal novel modes of regulating Stub1 activity and Foxp3 protein downregulation. Detailed assessment of physiological Stub1 induction and its impact on Foxp3 and Treg function is predicted to demonstrate a potent therapeutic application. Use of Stub1- activators in combination with proven checkpoint targeting agents may yield even better anti-tumor efficacy.
项目概要 肿瘤细胞利用免疫调节机制来逃避宿主防御的检测和根除。 Foxp3+CD4+CD25+调节性T细胞(Treg)介导的免疫抑制对于免疫逃避至关重要 肿瘤细胞和成功的肿瘤免疫治疗的障碍。因此,破坏 Treg 功能的能力是 具有重要的治疗意义。我们和其他人最近的工作揭示了关键的 Treg 转录因子, Foxp3 受到多聚泛素化依赖性翻译后调控。特别是,我们发现了E3 泛素连接酶 Stub1 是响应一系列应激信号而诱导的,可促进泛素连接酶 Stub1 的降解 Foxp3 为 Treg 抑制的动态调节提供了潜在的靶点。在当前的提案中,我们是 寻求:1) 剖析 Stub1 表达及其翻译后相关的分子信号通路 修改; 2) 了解生理性Stub1诱导和基因缺失对Treg的影响 细胞稳态、分化和功能; 3) 测试 Foxp3 泛素化的药理学激活剂 破坏癌症环境中免疫抑制的新型免疫治疗策略。这些研究将 扩大我们对翻译后 Foxp3 调控机制的理解。具体来说,我们将 进一步探索决定 Stub1 活性和表达的途径,包括以前未被重视的途径 连接酶被激酶 GS3Kβ 磷酸化。为此,我们将利用生化方法 体外和体内 Treg 功能的良好表征模型,以确定消除这些功能的后果 途径。此外,Foxp3 的 Stub1/泛素依赖性途径的药理学修饰剂 降解(在药物筛选和之前的研究中确定)将被测试作为免疫破坏者的功效 抑制——抗癌免疫治疗的主要障碍。此次审查将以积极的方式进行 鼠黑色素瘤模型(体内)以及从健康人体内获得的人类白细胞的离体研究 捐赠者和晚期癌症患者。在此过程中,我们将确定潜在的治疗应用 调节 Stub1 活性以增强抗肿瘤免疫力。我们的实验可能揭示新的调节模式 Stub1 活性和 Foxp3 蛋白下调。 Stub1 生理诱导的详细评估及其 对 Foxp3 和 Treg 功能的影响预计将证明其具有有效的治疗应用。使用 Stub1- 激活剂与经过验证的检查点靶向剂相结合可能会产生更好的抗肿瘤功效。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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DREW M. PARDOLL其他文献

DREW M. PARDOLL的其他文献

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{{ truncateString('DREW M. PARDOLL', 18)}}的其他基金

Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy
YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗
  • 批准号:
    10547779
  • 财政年份:
    2018
  • 资助金额:
    $ 37.91万
  • 项目类别:
Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy
YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗
  • 批准号:
    10330418
  • 财政年份:
    2018
  • 资助金额:
    $ 37.91万
  • 项目类别:
The Role of EOS in Regulatory T-cell Biology.
EOS 在调节性 T 细胞生物学中的作用。
  • 批准号:
    8490291
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
TH17炎症诱导的结肠癌发生机制
  • 批准号:
    8657874
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
The Role of EOS in Regulatory T-cell Biology.
EOS 在调节性 T 细胞生物学中的作用。
  • 批准号:
    8683077
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
TH17炎症诱导的结肠癌发生机制
  • 批准号:
    8105255
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis
产肠毒素脆弱拟杆菌:结肠癌发生的细菌启动子
  • 批准号:
    8707985
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
PD-1/PD-L1 modulation in cancer therapy
癌症治疗中的 PD-1/PD-L1 调节
  • 批准号:
    10355495
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
PD-1/PD-L1 modulation in cancer therapy
癌症治疗中的 PD-1/PD-L1 调节
  • 批准号:
    9188057
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis
产肠毒素脆弱拟杆菌:结肠癌发生的细菌启动子
  • 批准号:
    8137121
  • 财政年份:
    2010
  • 资助金额:
    $ 37.91万
  • 项目类别:
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