The tumor ecosystem in cancer progression and immunotherapeutic response

项目II.癌症进展中的肿瘤生态系统和免疫治疗反应 项目总结 这个项目的目标是确定癌症和免疫细胞之间的生态相互作用。 癌症动力学和治疗反应。我们从肿瘤可以被认为是一种 生态系统或器官，其中多种附属细胞类型相互连接并相互通信 以及作为它们的客户的肿瘤细胞。通过对功能模块的系统分析和建模 肿瘤生态系统中不同尺度上的相互作用，包括细胞、蛋白质和基因表达 群体和单细胞水平的动态这项提案将寻求确定关键的细胞和分子 肿瘤微环境中的调节元件及其治疗的潜在操作手段 利益。我们将探索多种辅助细胞类型和肿瘤细胞的特征及其之间的关系 小鼠和人类癌症患者皮肤癌和肺癌的实验模型(目标1)。附属品 细胞包括髓系细胞、树突状细胞、固有淋巴样细胞(ILC)、中性粒细胞、嗜酸性粒细胞、内皮细胞 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、CD4和CD8T细胞及其特化亚群。我们将使用微扰 肿瘤生态对小鼠和人肿瘤进展的影响 免疫治疗方式包括PD1和CTLA4阻断和Treg细胞耗尽。网络的影响 这些扰动将通过对细胞动力学和状态的综合分析进行评估 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)。到时候我们会的 通过模拟体外细胞与细胞的相互作用来验证肿瘤生态系统中的关键相互作用组件 组织模拟系统和使用基于试剂的模型的电子计算机(目标3)。 第1条

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