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Tumor and Immune Programming of Tumor-Associated Endothelium

肿瘤和肿瘤相关内皮细胞的免疫编程

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘