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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：
10621205
负责人：
Andrew Carl Dudley
金额：
$ 38.95万
依托单位：
UNIVERSITY OF VIRGINIA
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：
https://reporter.nih.gov/project-details/10621205
关键词：
Adhesions Angiogenesis Inhibitors Angiogenic Factor Area Attention Biological Assay Blood Vessels Brain Brain Neoplasms Breast Cancer Model CD8-Positive T-Lymphocytes Cancer Cell Growth Cell Adhesion Molecules Cell Communication Cell Line Cell Proliferation Cell Survival Cell division Cell physiology Cells Coculture Techniques Complex Cues Cyclic AMP-Dependent Protein Kinases Cyclin-Dependent Kinase Inhibitor Cytotoxic T-Lymphocytes DNA Methylation DNA Modification Methylases DNA delivery Development E-Selectin Endothelial Cells Endothelium Environment Enzymes Epigenetic Process Excision FGF2 gene Fibroblast Growth Factor Receptors Flow Cytometry Gatekeeping Gene Silencing Genes Genetic Genetically Engineered Mouse Goals Growth Growth Factor Heterogeneity Human Immune Immune Evasion Immune system Immunologic Surveillance Immunosuppression Immunotherapy Impairment In Vitro Infiltration Interferon Type II Investments Label Link Lymphocyte Depletion Mediating Metastatic malignant neoplasm to brain Methylation Microfluidic Microchips Modeling Morphogenesis Mus Neoplasm Metastasis Neoplasms in Vascular Tissue Normal tissue morphology Pathway interactions Penetration Perfusion Permeability Play Positioning Attribute Primary Neoplasm Proliferating Protein Kinase C Research Personnel Role Shapes Small Interfering RNA Solid Neoplasm Specific qualifier value Structure T-Lymphocyte TNF gene Tropism Tumor Biology Tumor Burden Tumor Immunity Tyrosine Kinase Inhibitor Work bioluminescence imaging blood vessel development cancer cell cancer immunotherapy cancer survival chemokine combinatorial derepression immune cell infiltrate immune checkpoint blockade immunosuppressed improved inhibitor interest loss of function lymphocyte trafficking malignant breast neoplasm methylation pattern monolayer mouse model nanoparticle neoplastic cell neovascularization recruit self-renewal single-cell RNA sequencing stem cell self renewal stem cells treatment strategy tumor tumor growth tumor microenvironment tumor progression tumor-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（EC）排列在血管内，促进生长并支持癌细胞的传播和存活。肿瘤血管系统也是控制肿瘤的看门人免疫细胞进出肿瘤微环境的通道。我们最近使用单细胞RNA 测序 (sc-RNAseq) 来表征乳腺肿瘤模型中的 EC 异质性；从这些研究中，我们将我们的注意力转向 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其在分裂细胞中重建甲基化模式的能力来进行自我更新，但在其中的作用尚不清楚调节肿瘤中的 EC 功能。使用 EC 中条件性删除 DNMT1 的小鼠（DNMT1iECKO 小鼠），我们显示出对肿瘤生长和转移播种的抑制以及血管复杂性/分支的减少。我们提出这些影响是由于甲基化依赖性 EC 规范的丧失所致 neovascularization and are due to de-repression of Th1 chemokines (e.g. Cxcl9/Cxcl10, and Cxcl11) and cell EC 中的粘附分子（例如 Vcam1、Icam1/2 和 E-选择素）可募集并保留细胞毒性 T- 淋巴细胞损害肿瘤生长。在目标 1 中，我们将使用 DNMT1iECKO 小鼠和血管亲和性纳米颗粒确定靶向 DNMT1 如何调节癌症期间 EC 形态发生、灌注和渗透性细胞存活。在目标 2 中，我们将使用转移模型来评估血管 DNMT1 如何塑造肿瘤免疫微环境通过其调节细胞粘附分子 (CAM) 和 CTL 动员的能力 EC 中的趋化因子。在目标 3 中，我们将研究 FGF2/DNMT1 轴的免疫抑制机制触发肿瘤相关 EC 中 CAM 和趋化因子甲基化诱导的沉默。完成我们的目标是，我们组建了一支在 DNA 甲基化 (S. Bhatnager)、肿瘤领域具有专业知识的研究人员团队免疫微环境（V. Engelhard），以及开发微流体装置来研究 EC 到 T 细胞相互作用（R. Kamm）。总之，我们的研究描绘了一个完全未经探索的领域；即，识别甲基化依赖性途径如何调节复杂的功能多样性、规范和肿瘤相关 EC 的免疫抑制特征。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vascular Mimicry: Concepts and Implications for Anti-Angiogenic Therapy.

DOI：
10.2174/2211552811201020133
发表时间：
2012-06-01
期刊：
Current angiogenesis
影响因子：
0
作者：
Dunleavey JM;Dudley AC
通讯作者：
Dudley AC

Pathological angiogenesis: mechanisms and therapeutic strategies.

DOI：
10.1007/s10456-023-09876-7
发表时间：
2023-08
期刊：
Angiogenesis
影响因子：
9.8
作者：
通讯作者：

Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

DOI：
10.1158/1078-0432.ccr-14-0493
发表时间：
2014-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Song G;Darr DB;Santos CM;Ross M;Valdivia A;Jordan JL;Midkiff BR;Cohen S;Nikolaishvili-Feinberg N;Miller CR;Tarrant TK;Rogers AB;Dudley AC;Perou CM;Zamboni WC
通讯作者：
Zamboni WC

Concise review: Vascular stem cells and tumor angiogenesis.

DOI：
10.1002/stem.583
发表时间：
2011-02
期刊：
STEM CELLS
影响因子：
5.2
作者：
Melero-Martin, Juan M.;Dudley, Andrew C.
通讯作者：
Dudley, Andrew C.

TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation.

DOI：
10.1038/srep14257
发表时间：
2015-09-21
期刊：
Scientific reports
影响因子：
4.6
作者：
Thoppil RJ;Adapala RK;Cappelli HC;Kondeti V;Dudley AC;Gary Meszaros J;Paruchuri S;Thodeti CK
通讯作者：
Thodeti CK