Hijacking the Blimp1-Neuritin Axis to Promote Cancer by Follicular Regulatory T-cells
劫持 Blimp1-Neuritin 轴通过滤泡调节 T 细胞促进癌症
基本信息
- 批准号:10629053
- 负责人:
- 金额:$ 20.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAdoptive TransferAreaAutonomic DysfunctionAutonomic nervous systemBiological AssayCancer PatientCellsFOXP3 geneFosteringFrequenciesGoalsHormonesHumanImmuneImmune EvasionImmune systemImmunofluorescence ImmunologicImmunotherapeutic agentIn VitroInfiltrationInvestigationLocationMalignant - descriptorMalignant NeoplasmsModelingMusNatureNeoplasm MetastasisNerveNerve FibersPRDM1 genePeripheralPeripheral NervesPsychological StressRegulationRegulatory T-LymphocyteReportingResearchRiskRoleStainsTestingTissuesTumor ImmunityTumor PromotionTumor-Infiltrating LymphocytesTumor-associated macrophagesanticancer researchaxonal sproutinggenetic signaturein vivoinnovationinsightnerve supplyneurofilamentneuroregulationneurotrophic factorpatient prognosisreconstitutionresponseretroviral-mediatedtherapy resistanttranscription factortumortumor growthtumor microenvironmenttumor progressiontumor-immune system interactionstumorigenesis
项目摘要
Project Summary
Recent studies have highlighted the vital role of nerves infiltrating the tumor microenvironment (TME) in
tumorigenesis and caner progression. The current research in this field is largely focused on the impact of
dysfunctions of autonomic nervous system or psychological stress-induced hormone network on the malignant
progression of cancer. The potential regulation of peripheral nerve system by immune cells in the TME, which
subsequently influences tumorigenesis, has not been extensively studied. The overall goal of this proposal is to
define how a specific Treg subset, called follicular regulatory T (TFR) cells, modulates the TME to promote cancer
by producing and utilizing a neurotrophic factor, which is an unexplored area in the field of cancer research. We
have recently reported the pro-tumoral activity of TFR cells, which depends on the expression of the transcription
factor Blimp1 (encoded by Prdm1). Further analysis revealed that higher tumoral TFR signatures along with
PRDM1 expression indicated increased malignancy and risk of metastasis in many cancers. Moreover,
intratumoral TFR cells compared to conventional Treg cells and their peripheral counterparts expressed higher
levels of neuritin (encoded by Nrn1), a neurotrophic factor implicated in tumorigenesis, while its mechanistic
action remains largely unclear. Notably, TFR signature and PRDM1 positively correlated with NRN1 expression
in cancer patients. Intratumoral TFR cells in mice with disrupted TFR suppression due to Foxp3-specific deletion
of Blimp1 had substantially reduced expression of neuritin. Most importantly, tumors from these mice and mice
lacking TFR cells had markedly reduced neurofilament accumulation compared to wild-type tumors, and
intratumoral TFR cells were enriched with gene signatures implicated in axonogenesis. We propose to define the
mechanisms by which TFR cells exploit the Blimp1-neuritin axis to regulate the TME and tumor progression, and
to define the capacity of TFR-derived neuritin in promoting axonogenesis in the tumor. Findings obtained here will
revolutionize our understanding of the tumor innervation and immunosuppressive TME, aiding in developing new
immunotherapeutic approaches to treat cancer.
项目摘要
最近的研究强调了神经在肿瘤微环境(TME)中的重要作用
肿瘤的发生和癌变。目前在这一领域的研究主要集中在
恶性肿瘤患者自主神经系统或心理应激诱导的激素网络功能障碍
癌症的进展。TME中免疫细胞对周围神经系统的电位调节
随后影响肿瘤的发生,还没有得到广泛的研究。这项提案的总体目标是
明确一个称为滤泡调节性T(TFR)细胞的特定Treg亚群如何调节TME以促进癌症
通过生产和利用一种神经营养因子,这在癌症研究领域是一个未被探索的领域。我们
最近报道了TFR细胞的促肿瘤活性,这依赖于转录的表达
因子Blimp1(由Prdm1编码)。进一步的分析显示,较高的肿瘤TFR签名以及
PRDM1的表达提示许多癌症的恶性程度和转移风险增加。此外,
瘤内TFR细胞与常规Treg细胞及其外周对应细胞相比表达更高
神经营养因子(由Nrn1编码)在肿瘤发生中的水平及其机制
行动在很大程度上仍不清楚。值得注意的是,TFR签名和PRDM1与NRN1的表达呈正相关
在癌症患者身上。Foxp3特异性缺失导致肿瘤内TFR抑制中断的小鼠肿瘤内TFR细胞
Blimp1组神经氨酸的表达显著减少。最重要的是,这些小鼠和小鼠的肿瘤
与野生型肿瘤相比,缺乏转铁蛋白受体细胞的神经丝堆积显著减少。
肿瘤内的TFR细胞富含与轴突形成有关的基因特征。我们建议定义
TFR细胞利用Blimp1-Neuritin轴调节TME和肿瘤进展的机制
目的:明确TFR来源的神经素在促进肿瘤轴突形成中的作用。在这里获得的发现将
彻底改变我们对肿瘤神经支配和免疫抑制TME的理解,有助于开发新的
治疗癌症的免疫治疗方法。
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)
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Jianmei Wu Leavenworth其他文献
Jianmei Wu Leavenworth的其他文献
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{{ truncateString('Jianmei Wu Leavenworth', 18)}}的其他基金
Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity
效应 Treg-B-抗体关系对中枢神经系统自身免疫调节的贡献
- 批准号:
10837917 - 财政年份:2020
- 资助金额:
$ 20.83万 - 项目类别:
Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity
效应 Treg-B-抗体关系对中枢神经系统自身免疫调节的贡献
- 批准号:
10621378 - 财政年份:2020
- 资助金额:
$ 20.83万 - 项目类别:
Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity
效应 Treg-B-抗体关系对中枢神经系统自身免疫调节的贡献
- 批准号:
10404044 - 财政年份:2020
- 资助金额:
$ 20.83万 - 项目类别:
Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity
效应 Treg-B-抗体关系对中枢神经系统自身免疫调节的贡献
- 批准号:
10804754 - 财政年份:2020
- 资助金额:
$ 20.83万 - 项目类别:
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