The tumor ecosystem in cancer progression and immunotherapeutic response

癌症进展和免疫治疗反应中的肿瘤生态系统

• 批准号: 9980809
• 负责人: Alexander Y Rudensky
• 金额: $ 63.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-26 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980809
• 关键词: Adaptive Immune System; Antigen-Presenting Cells; Biological; Biopsy; Blood; CD8-Positive T-Lymphocytes; CTLA4 blockade; Cancer Model; Cancer Patient; Cell Communication; Cell model; Cells; Client; Clinical; Communication; Computer Models; Data; Data Set; Dendritic Cells; Ecology; Ecosystem; Endothelial Cells; Epithelial Cells; Experimental Models; Fibroblasts; Gene Expression; Gene Expression Profiling; Goals; Hepatocyte; Human; Immune; Immunology; Immunotherapeutic agent; In Vitro; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Memorial Sloan-Kettering Cancer Center; Modality; Modeling; Modeling of Functional Interactions; Molecular; Mus; Myeloid Cells; NCI Center for Cancer Research; Natural Killer Cells; Organ; Organism; Outcome; PD-1 blockade; Patients; Physiological; Population; Regulatory Element; Regulatory T-Lymphocyte; Role; Skin Cancer; Smooth Muscle Myocytes; Stress; Structure; System; Systems Analysis; Therapeutic; Tissues; Tumor Immunity; Validation; alveolar epithelium; base; cancer immunotherapeutics; cell type; eosinophil; high throughput analysis; in silico; in vitro Model; macrophage; mathematical model; melanocyte; melanoma; mimetics; mouse model; neoplastic cell; neutrophil; novel; predictive modeling; protein expression; protein metabolite; response; tumor; tumor microenvironment; tumor progression

Project II. The tumor ecosystem in cancer progression and immunotherapeutic response PROJECT SUMMARY The goal of this project is to identify the ecological interactions between cancer and immune cells that govern cancer dynamics and response to therapy. We start from the idea that a tumor can be considered an ecosystem or organ, where multiple accessory cell types are interconnected and communicate with each other and with tumor cells, which serve as their clients. Through systems analysis and modeling of functional interactions in the tumor ecosystem on different scales including cellular, protein, and gene expression dynamics at a population and single cell levels this proposal will seek to identify key cellular and molecular regulatory elements in the tumor microenvironment and potential means of their manipulation for therapeutic benefit. We will explore features of, and relationships between, multiple accessory cell types and tumor cells, in experimental models of skin and lung cancer in mice and in human cancer patients (Aim 1). The accessory cells include myeloid cells, dendritic cells, innate lymphoid cells (ILC), neutrophils, eosinophils, endothelial cells, fibroblasts, and regulatory T (Treg) cells. We will also investigate features of mediators of anti-tumor immunity including NK cells, CD4 and CD8 T cells and their specialized subsets. We will use perturbation of the tumor ecology impacting its progression in mice and human patients by established and novel immunotherapeutic modalities including PD1 and CTLA4 blockade and Treg cell depletion. The impact of these perturbations will be assessed through comprehensive analysis of cellular dynamics and states in relation to biological and clinical outcomes to generate predictive models from the data (Aim 2). We will then validate key interaction components in the tumor ecosystem by modeling cell-cell interactions in vitro using tissue mimetic systems and in silico using agent-based models (Aim 3).   1

项目二.肿瘤生态系统在肿瘤进展和免疫应答中的作用 项目摘要 该项目的目标是确定癌症和免疫细胞之间的生态相互作用， 癌症动力学和对治疗的反应。我们从肿瘤可以被认为是 生态系统或器官，其中多种附属细胞类型相互连接并相互交流 肿瘤细胞也是它们的客户。通过系统分析和功能建模， 肿瘤生态系统中不同尺度的相互作用，包括细胞、蛋白质和基因表达 在群体和单细胞水平的动力学，该建议将寻求确定关键的细胞和分子 肿瘤微环境中的调节元件以及操纵它们用于治疗的潜在手段 效益我们将探讨多种辅助细胞类型和肿瘤细胞之间的特征和关系， 小鼠和人类癌症患者的皮肤癌和肺癌实验模型（目的1）。附件 细胞包括骨髓细胞、树突细胞、先天性淋巴样细胞（ILC）、嗜中性粒细胞、嗜酸性粒细胞、内皮细胞、巨噬细胞和巨噬细胞。 细胞、成纤维细胞和调节性T（Treg）细胞。我们还将研究抗肿瘤介质的特性 免疫包括NK细胞、CD 4和CD 8 T细胞及其特化亚群。我们将使用扰动 肿瘤生态学影响其在小鼠和人类患者中的进展， 免疫治疗模式包括PD 1和CTLA 4阻断和Treg细胞耗竭。的影响 这些扰动将通过对细胞动力学和状态的综合分析来评估， 与生物学和临床结果的关系，以根据数据生成预测模型（目标2）。然后我们将 通过使用体外细胞-细胞相互作用建模，验证肿瘤生态系统中的关键相互作用组分 组织模拟系统和使用基于代理的模型的计算机模拟（目标3）。   1