NGF recruits nerve fibers to reprogram an immunosuppressive microenvironment in melanoma

NGF 招募神经纤维来重新编程黑色素瘤中的免疫抑制微环境

基本信息

  • 批准号:
    10088428
  • 负责人:
  • 金额:
    $ 46.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Nerve infiltration has been implicated in the formation and progression of several solid tumor types including prostate, gastric, and pancreatic cancers. However, despite its neural origin, melanoma innervation has not been previously reported. In our preliminary studies, we discovered that melanoma tumor tissues from patient samples and mouse models are highly innervated. This innervation is dependent on tumor cell expression of nerve growth factor (NGF), as targeted NGF depletion eliminates intratumoral nerve fibers. Importantly, melanoma denervation via NGF knockdown or chemical sympathectomy dramatically reduces tumor burdens by remodeling the tumor microenvironment (TME). This TME reprogramming is associated with increased cytokine and chemokine expression, CD103+ DC activation, and CD8+ T cell recruitment, suggesting that NGF or nerve-derived neurotransmitters support tumor growth by suppressing antitumor immunity. Importantly, we confirmed this inverse correlation between tumor innervation and inflammation using clinical samples: melanomas expressing low levels of NGF are immunologically hot and associated with improved patient survival. These findings inspire our central hypothesis that NGF-mediated innervation of the tumor microenvironment can be exploited pharmacologically to reverse immunosuppression. In this study, we will test this hypothesis with the following three aims: Aim 1 will dissect molecular mechanisms of NGF-mediated remodeling of the intratumor immune microenvironment. Aim 2 will dissect molecular mechanisms by which NGF regulates T cell activation. Aim 3 will determine the pre-clinical efficacy of a therapeutic strategy combining NGF axis inhibition and immune checkpoint blockade against melanoma. Findings from the proposed studies will lay the foundation upon which potential combinational therapies can be developed to combat this disease.
神经浸润与几种实体瘤的形成和发展有关 包括前列腺癌、胃癌和胰腺癌。然而,尽管它的神经起源,黑色素瘤, 神经支配以前没有报道。在我们的初步研究中,我们发现黑色素瘤 来自患者样品和小鼠模型的肿瘤组织高度神经支配。这种神经支配 依赖于神经生长因子(NGF)的肿瘤细胞表达,因为靶向的NGF消耗消除了 肿瘤内神经纤维。重要的是,通过NGF敲除或化学方法对黑色素瘤进行去神经支配 交感神经切除术通过重塑肿瘤微环境(TME)显著降低肿瘤负荷。 这种TME重编程与增加的细胞因子和趋化因子表达、CD103+ DC 激活和CD8+ T细胞募集,表明NGF或神经源性神经递质支持 通过抑制抗肿瘤免疫来抑制肿瘤生长。重要的是,我们证实了这种逆相关性, 肿瘤神经支配和炎症之间的关系:表达低水平的 神经生长因子在免疫学上是热的,与改善患者生存相关。这些发现启发了我们 一个中心假设,即可以利用肿瘤微环境的NGF介导的神经支配 逆转免疫抑制。在这项研究中,我们将测试这一假设与 以下三个目标:目标1将剖析神经生长因子介导的重塑的分子机制, 肿瘤内免疫微环境。目的2将剖析神经生长因子调节的分子机制 T细胞活化。目的3将确定联合神经生长因子的治疗策略的临床前疗效 轴抑制和免疫检查点阻断。拟议研究的结果 将为开发潜在的组合疗法以对抗这种疾病奠定基础 疾病

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 }}

Qijing Li其他文献

Qijing Li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('Qijing Li', 18)}}的其他基金

Clinical Neuroimmunology of Vaccines in Brain Tumors
脑肿瘤疫苗的临床神经免疫学
  • 批准号:
    10348190
  • 财政年份:
    2021
  • 资助金额:
    $ 46.98万
  • 项目类别:
Synthetic lethality by targeting the core senescent mechanism in lung cancer.
针对肺癌核心衰老机制的综合致死率。
  • 批准号:
    10090580
  • 财政年份:
    2020
  • 资助金额:
    $ 46.98万
  • 项目类别:
Targeting UHRF1 in combinational immunotherapy
联合免疫疗法中靶向 UHRF1
  • 批准号:
    9763378
  • 财政年份:
    2019
  • 资助金额:
    $ 46.98万
  • 项目类别:
Targeting UHRF1 in combinational immunotherapy
联合免疫治疗中的靶向 UHRF1
  • 批准号:
    10055773
  • 财政年份:
    2019
  • 资助金额:
    $ 46.98万
  • 项目类别:
Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity
T细胞自身免疫的新型介质miR-19b的调节机制
  • 批准号:
    8969661
  • 财政年份:
    2011
  • 资助金额:
    $ 46.98万
  • 项目类别:
Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity
T细胞自身免疫的新型介质miR-19b的调节机制
  • 批准号:
    8598453
  • 财政年份:
    2011
  • 资助金额:
    $ 46.98万
  • 项目类别:
Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity
T细胞自身免疫的新型介质miR-19b的调节机制
  • 批准号:
    8383094
  • 财政年份:
    2011
  • 资助金额:
    $ 46.98万
  • 项目类别:
Harnessing microRNAs within miR-17-92 cluster for autoimmune intervention
利用 miR-17-92 簇内的 microRNA 进行自身免疫干预
  • 批准号:
    8312018
  • 财政年份:
    2011
  • 资助金额:
    $ 46.98万
  • 项目类别:
Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity
T细胞自身免疫的新型介质miR-19b的调节机制
  • 批准号:
    8234916
  • 财政年份:
    2011
  • 资助金额:
    $ 46.98万
  • 项目类别:

相似海外基金

MRI and Biological Markers of Acute E-Cigarette Exposure in Smokers and Vapers
吸烟者和电子烟使用者急性电子烟暴露的 MRI 和生物标志物
  • 批准号:
    10490338
  • 财政年份:
    2021
  • 资助金额:
    $ 46.98万
  • 项目类别:
MRI and Biological Markers of Acute E-Cigarette Exposure in Smokers and Vapers
吸烟者和电子烟使用者急性电子烟暴露的 MRI 和生物标志物
  • 批准号:
    10353104
  • 财政年份:
    2021
  • 资助金额:
    $ 46.98万
  • 项目类别:
Investigating pollution dynamics of swimming pool waters by means of chemical and biological markers
利用化学和生物标记物研究游泳池水体的污染动态
  • 批准号:
    21K04320
  • 财政年份:
    2021
  • 资助金额:
    $ 46.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
MRI and Biological Markers of Acute E-Cigarette Exposure in Smokers and Vapers
吸烟者和电子烟使用者急性电子烟暴露的 MRI 和生物标志物
  • 批准号:
    10688286
  • 财政年份:
    2021
  • 资助金额:
    $ 46.98万
  • 项目类别:
Novel biological markers for immunotherapy and comprehensive genetic analysis in thymic carcinoma
用于胸腺癌免疫治疗和综合遗传分析的新型生物标志物
  • 批准号:
    20K17755
  • 财政年份:
    2020
  • 资助金额:
    $ 46.98万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Examination of Biological Markers Associated with Neurobehavioral and Neuropsychological Outcomes in Military Veterans with a History of Traumatic Brain Injury
与有脑外伤史的退伍军人的神经行为和神经心理结果相关的生物标志物的检查
  • 批准号:
    10578649
  • 财政年份:
    2019
  • 资助金额:
    $ 46.98万
  • 项目类别:
Examination of Biological Markers Associated with Neurobehavioral and Neuropsychological Outcomes in Military Veterans with a History of Traumatic Brain Injury
与有脑外伤史的退伍军人的神经行为和神经心理结果相关的生物标志物的检查
  • 批准号:
    10295141
  • 财政年份:
    2019
  • 资助金额:
    $ 46.98万
  • 项目类别:
Examination of Biological Markers Associated with Neurobehavioral and Neuropsychological Outcomes in Military Veterans with a History of Traumatic Brain Injury
与有脑外伤史的退伍军人的神经行为和神经心理结果相关的生物标志物的检查
  • 批准号:
    10041708
  • 财政年份:
    2019
  • 资助金额:
    $ 46.98万
  • 项目类别:
Examination of Biological Markers Associated with Neurobehavioral and Neuropsychological Outcomes in Military Veterans with a History of Traumatic Brain Injury
与有脑外伤史的退伍军人的神经行为和神经心理结果相关的生物标志物的检查
  • 批准号:
    9776149
  • 财政年份:
    2019
  • 资助金额:
    $ 46.98万
  • 项目类别:
Combining biological and non-biological markers to develop a model predictive of treatment response for individuals with depression
结合生物和非生物标志物来开发预测抑郁症患者治疗反应的模型
  • 批准号:
    2063934
  • 财政年份:
    2018
  • 资助金额:
    $ 46.98万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了