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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：
10092966
负责人：
Andrew Carl Dudley
金额：
$ 36.34万
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/10092966
关键词：
Adhesions 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 Culture Techniques Cell Line Cell Proliferation Cell Survival Cell division Cell physiology Cells Coculture Techniques Complex Cues Cyclin-Dependent Kinase Inhibitor Cytotoxic T-Lymphocytes DNA 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 system Immunologic Surveillance Immunosuppression Immunotherapy Impairment In Vitro Interferon Type II 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 PRKCA gene Pathway interactions Perfusion Permeability Play Positioning Attribute Primary Neoplasm Protein Kinase C Repression Research Personnel Role Shapes Small Interfering RNA Solid Neoplasm Structure T-Lymphocyte TNF gene Tropism Tumor Biology Tumor Burden Tumor Immunity Tumor-infiltrating immune cells Tyrosine Kinase Inhibitor Work bioluminescence imaging blood vessel development cancer cell cancer immunotherapy cancer survival chemokine combinatorial immune checkpoint blockade immunosuppressed improved inhibitor/antagonist 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 stem cells transcriptome sequencing 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）排列在血管中，促进肿瘤生长并支持肿瘤生长。扩散和癌细胞的存活。肿瘤血管系统也是控制肿瘤细胞增殖的守门人。免疫细胞进出肿瘤微环境的通道。我们最近使用单细胞RNA 用sc-RNAseq技术来表征乳腺肿瘤模型中EC的异质性;从这些研究中，我们 DNA甲基转移酶1（DNMT 1）在干/祖细胞中具有明确的作用，通过其在分裂细胞中重新建立甲基化模式的能力进行自我更新，但在调节肿瘤中EC的功能。使用EC中DNMT 1条件性缺失的小鼠（DNMT 1 iECKO小鼠），我们显示了对肿瘤生长和转移性接种的抑制以及降低的血管复杂性/分支。我们我提出这些影响是由于甲基化依赖的EC规格的损失所需的新血管形成，并且是由于Th 1趋化因子（例如Cxc 19/Cxc 110和Cxc 111）和细胞因子的去抑制所致。粘附分子（如Vcam 1，Icam 1/2和E-选择素）在EC中募集和保留细胞毒性T细胞，淋巴细胞，以削弱肿瘤生长。在目标1中，我们将使用DNMT 1 iECKO小鼠和血管嗜性纳米颗粒确定靶向DNMT 1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DNMT 1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FGF 2/DNMT 1轴的免疫抑制机制其触发肿瘤相关EC中CAM和趋化因子的甲基化诱导沉默。完成为了实现我们的目标，我们组建了一个具有DNA甲基化专业知识的研究团队（S。Bhatnager），肿瘤免疫微环境（V. Engelhard），以及研究EC至T细胞的微流体装置的开发相互作用（R. Kamm）。总之，我们的研究描述了一个完全未探索的领域;即，识别甲基化依赖性途径如何调节复杂的功能多样性，规格，肿瘤相关EC的免疫抑制特征。