Tumor and Immune Programming of Tumor-AssociatedEndothelium

肿瘤和肿瘤相关内皮细胞的免疫编程

• 批准号: 10303033
• 负责人: EUGENE C BUTCHER
• 金额: $ 43.55万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303033
• 关键词: Abbreviations; Adhesions; Algorithmic Software; Algorithms; Antigens; Area; Atlases; Automobile Driving; Blood; Blood Vessels; Blood capillaries; Cancer Biology; Cell Adhesion Molecules; Cells; Cytometry; Data; Development; Endothelial Cells; Endothelium; Environment; Flow Cytometry; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Goals; Growth; High Endothelial Venule; Histology; Homeostasis; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Immunotherapy; Inflammation; Investigation; Kinetics; Label; Lead; Leukocytes; Location; Lymphocyte; MCAM gene; Malignant Neoplasms; Maps; Modeling; Molecular; Molecular Profiling; Monitor; Mucous Membrane; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Transplantation; Nutrient; Outcome; PNAd; Pathologic; Pathway interactions; Peripheral; Phenotype; Physiologic pulse; Population; Proliferating; Proteomics; Regulation; Reporter; Resistance; Rest; Role; STEM program; Selectins; Specificity; System; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tissue imaging; Tissues; Tumor Angiogenesis; Tumor Biology; Tumor Expansion; Tumor Immunity; Tumor Stem Cells; Tumor-Associated Vasculature; Vascular Endothelial Cell; angiogenesis; bioinformatics tool; cancer immunotherapy; cell transformation; directed differentiation; gene network; high dimensionality; immune checkpoint blockade; improved outcome; innovation; lymph nodes; molecular modeling; molecular phenotype; neoplasm immunotherapy; nestin protein; network models; notch protein; novel; novel therapeutic intervention; postcapillary venule; predictive modeling; progenitor; programs; recombinase; recruit; response; role model; single-cell RNA sequencing; stem; stem cells; stem-like cell; tertiary lymphoid organ; tool; trafficking; transcriptomics; tumor; tumor growth; tumor immunology; tumorigenesis; vascular addressins; venule

PROJECT SUMMARY/ABSTRACT Blood vascular endothelial cells (BEC) control tumor growth through angiogenesis and differentiation of support vessels, and direct the host immune response to cancer by regulating immune cell recruitment from the blood. Recent studies emphasize the importance of specialized subsets of BEC in tumor biology, including high endothelial venules (HEV, vessels specialized for lymphocyte recruitment) which help direct effective tumor immunity. In spite of their central role in tumor biology, little is known about the BEC at the molecular level, mechanisms that regulate tumor angiogenesis are poorly understood, and the precursors that give rise to angiogenic tumor EC and to tumor-associated leukocyte-recruiting vessels remain to be determined. Under Aim 1 we will apply state-of-the-art single cell high dimensional mass label (CyTOF) flow cytometry and single cell RNAseq analyses to uncover the diversity of EC subsets in tumors and their environment, define the kinetics and subset-specificity of proliferative responses during tumor angiogenesis, and monitor the emergence and maturation of functional HEV and other post capillary venules (PCV) for immune cell traffic. Trajectory analyses will reveal developmental relationships of identified subsets including candidate progenitors, and immunofluorescence histology and confocal tissue imaging will define their location within the tumor and associated vasculature. Single cell BEC signatures will be mapped to the tumor vasculature using quantitative tissue immunohistology. Under Aim 2, innovative fate mapping approaches will elucidate precursor-product relationships among BEC subsets and will define clonal contributions of precursors to angiogenic tumor EC, to specialized EC of support vessels, and to high endothelium. Aim 3 will mine transcriptional profiles of induced EC subsets and apply pan-EC and EC subset-specific inducible gene targeting systems to define pathways and mechanisms that control progenitor cell and amplifying tumor EC activation, and that direct the differentiation of tumor-associated HEV. Novel bioinformatics tools will be applied to uncover transcriptional programs and pathways that induce recruiting vessels in settings of immunotherapy. Generation of a comprehensive atlas of blood endothelial cell subsets, molecular phenotypes and responses to tumorigenesis will open up new areas of investigation in cancer biology and immunology. Elucidation of the mechanisms of endothelial cell specialization and homeostasis, including mechanisms regulating endothelial cells that control lymphocyte traffic into tumors, may lead to novel targets and approaches to enhance cancer immunotherapies.

项目概要/摘要 血管内皮细胞（BEC）通过血管生成和分化来控制肿瘤生长 支持血管，并通过调节免疫细胞的募集来指导宿主对癌症的免疫反应 血。最近的研究强调了 BEC 特殊亚群在肿瘤生物学中的重要性，包括 高内皮微静脉（HEV，专门用于淋巴细胞募集的血管）有助于直接有效 肿瘤免疫。尽管 BEC 在肿瘤生物学中发挥着核心作用，但人们对 BEC 的分子水平知之甚少。 水平，调节肿瘤血管生成的机制知之甚少，并且产生的前体 血管生成性肿瘤 EC 和肿瘤相关白细胞募集血管的作用仍有待确定。 在目标 1 下，我们将应用最先进的单细胞高维质量标签 (CyTOF) 流式细胞术 和单细胞 RNAseq 分析以揭示肿瘤及其环境中 EC 亚群的多样性， 定义肿瘤血管生成过程中增殖反应的动力学和子集特异性，并监测 用于免疫细胞运输的功能性 HEV 和其他毛细血管后微静脉 (PCV) 的出现和成熟。 轨迹分析将揭示已识别子集的发展关系，包括候选者 祖细胞，免疫荧光组织学和共聚焦组织成像将确定它们在细胞内的位置 肿瘤和相关的脉管系统。单细胞 BEC 特征将使用以下方法映射到肿瘤脉管系统 定量组织免疫组织学。在目标 2 下，创新的命运图谱方法将阐明 BEC子集之间的前体-产物关系，并将定义前体对克隆的贡献 血管生成肿瘤 EC、支持血管的专门 EC、以及高内皮细胞。目标 3 将开采 诱导 EC 亚群的转录谱并应用泛 EC 和 EC 亚群特异性诱导基因 靶向系统来定义控制祖细胞和放大肿瘤 EC 的途径和机制 激活，并指导肿瘤相关 HEV 的分化。将应用新型生物信息学工具 揭示在免疫治疗环境中诱导血管募集的转录程序和途径。 生成血液内皮细胞亚群、分子表型和 对肿瘤发生的反应将开辟癌症生物学和免疫学的新研究领域。 阐明内皮细胞特化和稳态的机制，包括机制 调节控制淋巴细胞进入肿瘤的内皮细胞，可能会导致新的靶点和 增强癌症免疫治疗的方法。