Targeting the vasculature to enhance anti-tumor immunity
靶向血管系统增强抗肿瘤免疫力
基本信息
- 批准号:10092966
- 负责人:
- 金额:$ 36.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAngiogenic FactorAreaAttentionBiological AssayBlood VesselsBrainBrain NeoplasmsBreast Cancer ModelCD8-Positive T-LymphocytesCancer Cell GrowthCell Adhesion MoleculesCell CommunicationCell Culture TechniquesCell LineCell ProliferationCell SurvivalCell divisionCell physiologyCellsCoculture TechniquesComplexCuesCyclin-Dependent Kinase InhibitorCytotoxic T-LymphocytesDNADNA MethylationDNA Modification MethylasesDNA deliveryDevelopmentE-SelectinEndothelial CellsEndotheliumEnvironmentEnzymesEpigenetic ProcessExcisionFGF2 geneFibroblast Growth Factor ReceptorsFlow CytometryGatekeepingGene SilencingGenesGeneticGenetically Engineered MouseGoalsGrowthGrowth FactorHeterogeneityHumanImmuneImmune systemImmunologic SurveillanceImmunosuppressionImmunotherapyImpairmentIn VitroInterferon Type IILabelLinkLymphocyte DepletionMediatingMetastatic malignant neoplasm to brainMethylationMicrofluidic MicrochipsModelingMorphogenesisMusNeoplasm MetastasisNeoplasms in Vascular TissueNormal tissue morphologyPRKCA genePathway interactionsPerfusionPermeabilityPlayPositioning AttributePrimary NeoplasmProtein Kinase CRepressionResearch PersonnelRoleShapesSmall Interfering RNASolid NeoplasmStructureT-LymphocyteTNF geneTropismTumor BiologyTumor BurdenTumor ImmunityTumor-infiltrating immune cellsTyrosine Kinase InhibitorWorkbioluminescence imagingblood vessel developmentcancer cellcancer immunotherapycancer survivalchemokinecombinatorialimmune checkpoint blockadeimmunosuppressedimprovedinhibitor/antagonistinterestloss of functionlymphocyte traffickingmalignant breast neoplasmmethylation patternmonolayermouse modelnanoparticleneoplastic cellneovascularizationrecruitself-renewalsingle-cell RNA sequencingstemstem cellstranscriptome sequencingtreatment strategytumortumor growthtumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
Tumor-associated endothelial cells (ECs) line the blood vessels that promote the growth and support the
dissemination and survival of cancer cells. The tumor vasculature is also a gatekeeper that controls the
passage of immune cells both into and out of the tumor microenvironment. We recently used single cell RNA
sequencing (sc-RNAseq) to characterize EC heterogeneity in a mammary tumor model; from these studies, we
turned our attention to DNA methyltransferase1 (DNMT1) which has well-defined roles in stem/progenitor cell
self-renewal via it's ability to re-establish patterns of methylation in dividing cells, but no known role in
regulating EC function in tumors. Using mice with conditional deletion of DNMT1 in ECs (DNMT1iECKO mice),
we show inhibition of tumor growth and metastatic seeding and reduced vessel complexity/branching. We
propose these effects are due to a loss of methylation-dependent EC specification required for
neovascularization and are due to de-repression of Th1 chemokines (e.g. Cxcl9/Cxcl10, and Cxcl11) and cell
adhesion molecules (e.g. Vcam1, Icam1/2, and E-selectin) in ECs that recruit and retain cytotoxic T-
lymphocytes to impair tumor growth. In aim 1 we will use DNMT1iECKO mice and vascular-tropic nanoparticles
to determine how targeting DNMT1 regulates EC morphogenesis, perfusion, and permeability during cancer
cell survival. In aim 2 we will use metastasis models to assess how vascular DNMT1 shapes the tumor
immune microenvironment via its ability to regulate cell adhesion molecules (CAMs) and CTL-mobilizing
chemokines in ECs. In aim 3 we will examine mechanisms of immune suppression by a FGF2/DNMT1 axis
that triggers methylation-induced silencing of CAMs and chemokines in tumor-associated ECs. To complete
our goals, we have assembled a team of investigators with expertise in DNA methylation (S. Bhatnager), tumor
immune micro environments (V. Engelhard), and the development of microfluidics devices to study EC-to-T-cell
interactions (R. Kamm). Together, our study characterizes a completely unexplored area; namely, identifying
how methylation-dependent pathways regulate the complex functional diversity, specification, and
immunosuppressive features of tumor-associated ECs.
肿瘤相关内皮细胞(ECs)排列在促进生长和支持血管生长的血管中
癌细胞的扩散和存活。肿瘤血管系统也是一个把关人,控制着
免疫细胞进出肿瘤微环境的通道。我们最近使用了单细胞RNA
测序(sc-RNAseq)以表征乳腺肿瘤模型中EC的异质性;从这些研究中,我们
我们将注意力转向DNA甲基转移酶1(DNMT1),它在干细胞/祖细胞中具有明确的作用
通过它在分裂细胞中重新建立甲基化模式的能力进行自我更新,但在
调节肿瘤内皮细胞的功能。使用内皮细胞中DNMT1有条件缺失的小鼠(DNMT1iECKO小鼠),
我们显示了对肿瘤生长和转移种植的抑制以及减少血管复杂性/分支。我们
提出这些影响是由于丢失了所需的依赖甲基化的EC规范
血管新生是由于Th1趋化因子(如Cxcl9/Cxcl10和Cxcl11)和细胞的抑制
内皮细胞中的黏附分子(如Vcam1、Icam1/2和E-选择素)招募和保留细胞毒性T细胞-
淋巴细胞会损害肿瘤的生长。在目标1中,我们将使用DNMT1iECKO小鼠和亲血管纳米颗粒
确定靶向DNMT1如何在肿瘤过程中调节EC的形态发生、灌流和通透性
细胞存活。在目标2中,我们将使用转移模型来评估血管DNMT1如何塑造肿瘤
调节细胞黏附分子和CTL动员的免疫微环境
内皮细胞中的趋化因子。在目标3中,我们将研究FGF2/DNMT1轴的免疫抑制机制
这触发了甲基化诱导肿瘤相关内皮细胞中的CaM和趋化因子的沉默。要完成
为了实现我们的目标,我们组建了一支在DNA甲基化(S.Bhatnager)、肿瘤方面具有专业知识的研究团队
免疫微环境(V.Engelhard),以及研究EC-to-T细胞的微流控设备的发展
互动(R.Kamm)。总而言之,我们的研究描述了一个完全未开发的区域的特征;即,确定
甲基化依赖的途径如何调节复杂的功能多样性、规范和
肿瘤相关内皮细胞的免疫抑制特性。
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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Andrew Carl Dudley其他文献
Andrew Carl Dudley的其他文献
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{{ truncateString('Andrew Carl Dudley', 18)}}的其他基金
Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices
肿瘤内皮细胞对促转移纤维蛋白基质的调节
- 批准号:
10356164 - 财政年份:2021
- 资助金额:
$ 36.34万 - 项目类别:
Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices
肿瘤内皮细胞对促转移纤维蛋白基质的调节
- 批准号:
10179715 - 财政年份:2021
- 资助金额:
$ 36.34万 - 项目类别:
Tumor Endothelial Cell Regulation of Pro-Metastatic Fibrin Matrices
肿瘤内皮细胞对促转移纤维蛋白基质的调节
- 批准号:
10573196 - 财政年份:2021
- 资助金额:
$ 36.34万 - 项目类别:
Mechanisms of tumor escape from anti-angiogenic therapy
肿瘤逃避抗血管生成治疗的机制
- 批准号:
8693221 - 财政年份:2014
- 资助金额:
$ 36.34万 - 项目类别:
Mechanisms of tumor escape from anti-angiogenic therapy
肿瘤逃避抗血管生成治疗的机制
- 批准号:
8887312 - 财政年份:2014
- 资助金额:
$ 36.34万 - 项目类别:
Targeting the vasculature to enhance anti-tumor immunity
靶向血管系统增强抗肿瘤免疫力
- 批准号:
10399410 - 财政年份:2014
- 资助金额:
$ 36.34万 - 项目类别:
Targeting the vasculature to enhance anti-tumor immunity
靶向血管系统增强抗肿瘤免疫力
- 批准号:
10621205 - 财政年份:2014
- 资助金额:
$ 36.34万 - 项目类别:
Characterizing tumor endothelial cell abnormalities to develop rational anti-angi
表征肿瘤内皮细胞异常以开发合理的抗血管治疗
- 批准号:
7708266 - 财政年份:2009
- 资助金额:
$ 36.34万 - 项目类别:
Characterizing tumor endothelial cell abnormalities to develop rational anti-angi
表征肿瘤内皮细胞异常以开发合理的抗血管治疗
- 批准号:
8231654 - 财政年份:2009
- 资助金额:
$ 36.34万 - 项目类别:
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