Tumor and Immune Programming of Tumor-Associated Endothelium

肿瘤和肿瘤相关内皮细胞的免疫编程

• 批准号: 10054980
• 负责人: EUGENE C BUTCHER
• 金额: $ 44.18万
• 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/10054980
• 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; Myelogenous; Myeloid 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; Suppressor-Effector T-Lymphocytes; 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; 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.

项目摘要/摘要 血管内皮细胞（BEC）通过血管生成和分化控制肿瘤的生长 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 鲜血。最近的研究强调了BEC专业亚集在肿瘤生物学中的重要性，包括 高内皮静脉（HEV，专门用于淋巴细胞募集的船只），有助于直接有效 肿瘤免疫。尽管它们在肿瘤生物学中具有核心作用，但对分子的BEC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 血管生成的肿瘤EC和与肿瘤相关的白细胞征收血管尚待确定。 在AIM 1下，我们将应用最先进的单细胞高维质量标签（Cytof）流式细胞仪 单细胞RNASEQ分析以发现肿瘤及其环境中ECSet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 用于免疫细胞流量的功能性HEV和其他毛细血管静脉（PCV）的出现和成熟。 轨迹分析将揭示包括候选人在内的已识别子集的发展关系 祖细胞，免疫荧光组织学和共聚焦组织成像将定义其在 肿瘤和相关的脉管系统。单细胞的签名将映射到使用肿瘤脉管系统 定量组织免疫组织学。在AIM 2下，创新的命运映射方法将阐明 BEC子集之间的前体产物关系关系，并将定义前体的克隆贡献 血管生成肿瘤EC，用于支撑血管的专业EC和高内皮。 AIM 3将是我的 诱导的EC子集的转录曲线，并应用PAN-EC和EC亚集特异性诱导基因 定位系统来定义控制祖细胞和扩增肿瘤EC的途径和机制 激活，并指导与肿瘤相关的HEV的分化。新颖的生物信息学工具将被应用 揭示在免疫疗法环境中诱导招募血管的转录程序和途径。 产生血液内皮细胞子集，分子表型和 对肿瘤发生的反应将为癌症生物学和免疫学方面的新调查领域开放。 阐明内皮细胞专业化和稳态的机制，包括机制 调节控制淋巴细胞流量到肿瘤的内皮细胞，可能导致新的靶标和 增强癌症免疫疗法的方法。