IDO1 and Immunotolerance in Glioblastoma

IDO1 和胶质母细胞瘤的免疫耐受

基本信息

项目摘要

ABSTRACT Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor in adults. Median survival for GBM patients is 14.6 months post-diagnosis. A consistent feature of GBM is the intratumoral presence of immunosuppressive regulatory T cells (Treg) that impair patient anti-GBM immune response, coincident with the expression of indoleamine 2,3 dioxygenase 1 (IDO1), a rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Utilizing the orthotopic syngeneic and immunocompetent GL261-C57BL6 engraftment model, I previously demonstrated that shRNA-mediated suppression of IDO1 expression in murine GBM cells significantly decreases intratumoral Treg accumulation coincident with a cytolytic T cell response leading to complete tumor regression. This observation prompted the investigation into pharmacologic inhibition of IDO1 as a means to therapeutically induce anti-GBM immunity. Surprisingly, however, the administration of IDO1 inhibitor had no effect on intratumoral Treg accumulation nor on animal subject survival. A hypothesis that provides an explanation for this paradox, addressing how genetic suppression-, but not pharmacologic inhibition- of IDO1, affects intratumoral Treg accumulation and effector T cell response against GBM, forms the basis of this proposal. Recently, my lab discovered that cells in the tumor microenvironment, but not GBM cells, are responsible for nearly all IDO1-mediated Trp to Kyn catabolism in the GL261-C57BL6 model. This observation, however, raises a question regarding the role of tumor cell-associated IDO1, whose genetic suppression promotes productive T cell response against tumor. A potential answer to this question has emerged in association with our discovery that IDO1 localizes to the nucleus in GBM cells. Based on these observations we propose to: 1) establish IDO1 cell type expression and catabolism in human GBM in situ, 2) investigate IDO1 expression and function in human GBM cells and to 3) determine the function of nuclear IDO1 in GBM cells. The proposed studies aim to investigate clinically-relevant questions and approaches that aim to reverse immunosuppression in glioma, which is the first step to the rational design of effective immunotherapy for patients with incurable brain cancer.
摘要 多形性胶质母细胞瘤(GBM)是成人最常见、最具侵袭性的脑肿瘤。中位数 GBM患者确诊后的生存期为14.6个月。基底膜的一个一贯特征是肿瘤内。 免疫抑制调节性T细胞(Treg)的存在会削弱患者的抗GBM免疫反应, 与吲哚胺2,3双加氧酶1(IDO1)的表达一致,IDO1是一种将 色氨酸(Trp)到犬尿氨酸(Kyn)。利用原位同源免疫活性基因GL261-C57BL6 在植入模型中,我以前证明了shRNA介导的IDO1在小鼠中的表达抑制 GBM细胞显著减少肿瘤内Treg蓄积与细胞溶解T细胞应答一致 导致肿瘤完全消退。这一观察结果促使对药物抑制的调查。 IDO1作为治疗性诱导抗GBM免疫的手段。然而,令人惊讶的是,政府 IDO1抑制剂对肿瘤内Treg蓄积和动物存活率均无影响。一种假设 为这一悖论提供了解释,解决了基因抑制--而不是药物抑制-- IDO1,影响瘤内Treg蓄积和效应T细胞对GBM的反应,形成了 这项提议。最近,我的实验室发现,肿瘤微环境中的细胞,而不是基底膜细胞,是 在GL261-C57BL6模型中,负责几乎所有IDO1介导的Trp到Kyn的分解代谢。这一观察结果, 然而,提出了一个关于肿瘤细胞相关IDO1的作用的问题,它的基因抑制 促进T细胞对肿瘤的生产性反应。这个问题的一个潜在答案已经出现在 与我们发现IDO1定位于GBM细胞的核有关。基于这些观察,我们 建议:1)建立人肾小球基底膜中IDO1的细胞类型表达和分解代谢;2)研究IDO1 核内IDO1在人GBM细胞中的表达和功能;3)决定核IDO1在GBM细胞中的功能。这个 拟议的研究旨在调查与临床相关的问题和方法,旨在逆转 胶质瘤的免疫抑制,这是合理设计有效的免疫治疗的第一步 患有无法治愈的脑癌。

项目成果

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

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Derek Alan Wainwright其他文献

Derek Alan Wainwright的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Derek Alan Wainwright', 18)}}的其他基金

Extratumoral biological determinants that decrease survival in older adults with glioblastoma
降低老年胶质母细胞瘤患者生存率的肿瘤外生物决定因素
  • 批准号:
    10741380
  • 财政年份:
    2023
  • 资助金额:
    $ 4.09万
  • 项目类别:
Aging, immunosenescence and glioblastoma
衰老、免疫衰老和胶质母细胞瘤
  • 批准号:
    10227148
  • 财政年份:
    2020
  • 资助金额:
    $ 4.09万
  • 项目类别:
Aging, immunosenescence and glioblastoma
衰老、免疫衰老和胶质母细胞瘤
  • 批准号:
    10403678
  • 财政年份:
    2020
  • 资助金额:
    $ 4.09万
  • 项目类别:
Aging, immunosenescence and glioblastoma
衰老、免疫衰老和胶质母细胞瘤
  • 批准号:
    10839567
  • 财政年份:
    2020
  • 资助金额:
    $ 4.09万
  • 项目类别:
Aging, immunosenescence and glioblastoma
衰老、免疫衰老和胶质母细胞瘤
  • 批准号:
    10039857
  • 财政年份:
    2020
  • 资助金额:
    $ 4.09万
  • 项目类别:
Simultaneous Radiotherapy with PD-1 and IDO1 Blockade for Overcoming Immune Suppression in Glioblastoma
PD-1 和 IDO1 阻断同时放疗克服胶质母细胞瘤的免疫抑制
  • 批准号:
    9570361
  • 财政年份:
    2018
  • 资助金额:
    $ 4.09万
  • 项目类别:
Simultaneous Radiotherapy with PD-1 and IDO1 Blockade for Overcoming Immune Suppression in Glioblastoma
PD-1 和 IDO1 阻断同时放疗克服胶质母细胞瘤的免疫抑制
  • 批准号:
    10224125
  • 财政年份:
    2018
  • 资助金额:
    $ 4.09万
  • 项目类别:
Simultaneous Radiotherapy with PD-1 and IDO1 Blockade for Overcoming Immune Suppression in Glioblastoma
PD-1 和 IDO1 阻断同时放疗克服胶质母细胞瘤的免疫抑制
  • 批准号:
    10478875
  • 财政年份:
    2018
  • 资助金额:
    $ 4.09万
  • 项目类别:
IDO1 and Immunotolerance in Glioblastoma
IDO1 和胶质母细胞瘤的免疫耐受
  • 批准号:
    9975916
  • 财政年份:
    2016
  • 资助金额:
    $ 4.09万
  • 项目类别:
IDO1 and Immunotolerance in Glioblastoma
IDO1 和胶质母细胞瘤的免疫耐受
  • 批准号:
    9321849
  • 财政年份:
    2016
  • 资助金额:
    $ 4.09万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
  • 批准号:
    2230829
  • 财政年份:
    2023
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 4.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了