Project 2: Spatial Architecture of Tumor-Mediated Immunosuppression

项目2：肿瘤介导的免疫抑制的空间架构

• 批准号: 9982082
• 负责人: GARRY P NOLAN
• 金额: $ 37.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982082
• 关键词: 3-Dimensional; Algorithms; Antibodies; Antigen Presentation; Apoptosis; Architecture; Area; Bar Codes; Biological Assay; Bone Marrow; Cancer Model; Cell Communication; Cell Cycle; Cell Survival; Cell physiology; Cells; Chelating Agents; Clinical; Communities; Core Facility; Cytometry; DNA Damage; DNA Intercalation; Data; Data Set; Databases; Development; Diagnostic; Disease; Disease model; Ensure; Environment; Epigenetic Process; Epitopes; Event; Fluorescence; Future; Genetic Transcription; Genomics; Goals; Head and Neck Squamous Cell Carcinoma; Hour; Human; Image; Imaging Device; Immune; Immune system; Immunologic Surveillance; Immunology; Immunosuppression; Immunotherapy; In Situ; Individual; International; Isotope Labeling; Isotopes; Knowledge; Laboratories; Lanthanoid Series Elements; Lymph Node Tissue; Malignant Neoplasms; Maps; Measures; Mediating; Medicine; Messenger RNA; Metabolism; Metals; Metastatic Neoplasm to Lymph Nodes; Minor; Modality; Multiplexed Ion Beam Imaging; Neck; Neoplasm Metastasis; Outcome; Paper; Periodicity; Pharmacologic Substance; Phase; Phenotype; Polymers; Population; Process; Proteins; Proteomics; Publishing; RNA; Reagent; Recording of previous events; Sampling; Series; Signal Transduction; Signaling Molecule; Slice; Solid Neoplasm; Squamous cell carcinoma; Stains; Surface; System; Systems Biology; Technology; Therapeutic; Time; Tissue imaging; Tissues; Tumor Cell Invasion; Visualization; Work; advanced disease; base; cancer imaging; carcinogenesis; cell type; cytokine; design; draining lymph node; drug development; high dimensionality; insight; instrument; interest; lymph nodes; male; melanoma; model building; mouse model; neoplastic cell; quantitative imaging; recruit; role model; tool; tumor; tumor growth; tumor progression

ABSTRACT/SUMMARY – Project 2: Spatial Architecture of Tumor-Mediated Immunosuppression Cancer progression is a disease of increasing disorder—yet a form of disorder with ordained stages of development. Beyond the internal genomic and epigenetic events that occur to drive a cell towards outright carcinogenesis and then metastasis, there co-exist the ordered events a cancer imposes on immune cells it encounters on its progression towards advanced disease. Induction of tolerance, avoidance of apoptosis, and even recruitment of the immune system to aid a tumor's growth are all poorly understood processes. We propose to undertake deep phenotyping of the 2D and 3D architecture of the tumor-lymph node micro- environment in human cancer & murine model counterparts —wherein it is thought that some of the initial phases of the tumor's avoidance and recruitment mechanisms are first implemented. How is the architecture of the immune environment disrupted in the face of tumor metastasis? Are their micro-communities changed (as defined by particular cell-cell interactions) whose presence or absence defines clinical outcomes during progression of the tumor? To this end we have developed a technology (ABSeq) that enables us to sensitively and quantitatively image tumors with 60 markers per 3-5 hours (scalable to 480 in a time-dependent manner). These markers are selected from a range of intracellular or surface epitopes (recognized by antibodies) or RNAs. The hypothesis is that an orchestrated corruption of immune surveillance is initiated by cancers as they progress, and that the micro-scale architecture of the lymph node (by way of which cells are talking to whom and what broader effects occur across the lymph node and beyond) is disrupted in a defined manner. Understanding of this process will result in mechanistic and therapeutic insights that are unavailable by other analysis modalities. Databases of 2D and 3D microenvironments will be publicly created and mined for associations that define the architectural changes in draining lymph nodes that occur as tumors progress and initiate tolerance. Perturbations that include immunotherapies will be implemented on the murine models to determine the further architectural changes that occur post therapy. Together the information will provide a first ever deep profiling of every major immune cell subset in lymph nodes as they re-architect themselves during metastatic establishment.

摘要/总结-项目2：肿瘤介导的免疫抑制的空间结构 癌症进展是一种疾病的增加障碍，但一种形式的障碍与预定的阶段， 发展除了内部的基因组和表观遗传事件，发生驱动细胞彻底 在癌症发生和转移的过程中，癌症对免疫细胞施加的有序事件共存， 在向晚期疾病进展时遇到的困难。诱导耐受性，避免细胞凋亡，以及 甚至免疫系统的募集来帮助肿瘤的生长都是知之甚少的过程。我们 建议对肿瘤淋巴结微结构的2D和3D结构进行深度表型分析， 在人类癌症中的环境和鼠模型对应物-其中认为一些初始的 首先实施肿瘤的回避和募集机制的阶段。建筑怎么样 肿瘤转移时免疫环境的破坏？他们的微社区是否改变了 (as由特定的细胞-细胞相互作用定义），其存在或不存在定义了在治疗期间的临床结果。 肿瘤的发展？为此，我们开发了一种技术（ABSeq），使我们能够灵敏地 并且每3-5小时用60个标记物对肿瘤进行定量成像（以时间依赖的方式可扩展到480个）。 这些标志物选自一系列细胞内或表面表位（被抗体识别）或 RNA。假设是，免疫监视的精心策划的腐败是由以下因素引发的： 癌症，因为他们的进展，并认为淋巴结的微观结构（通过它， 细胞在和谁说话，以及在淋巴结内外发生了什么更广泛的影响） 以一种确定的方式被破坏。了解这一过程将导致机械和治疗 其他分析模式无法提供的洞察力。2D和3D微环境的数据库将被 公开创建和挖掘的关联，定义引流淋巴结的架构变化， 随着肿瘤的进展而发生并引发耐受性。包括免疫疗法在内的干扰将是 在鼠模型上实施，以确定治疗后发生的进一步结构变化。 这些信息将共同提供淋巴中每个主要免疫细胞亚群的首次深度分析 节点，因为它们在转移建立期间重新构建自己。