Transparent Tumor Tomography (T3): Multi-Parameter 3D Imaging for Tumor Immunotherapy

透明肿瘤断层扫描 (T3)：用于肿瘤免疫治疗的多参数 3D 成像

• 批准号: 9314932
• 负责人: Steve Seung-Young Lee
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-10 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314932
• 关键词: Advanced Development; Aftercare; Antibodies; Antibody Response; Antibody Therapy; Antigens; Biological Assay; Biopsy; Blocking Antibodies; Blood Vessels; Brain; Cancer Biology; Cancer Diagnostics; Cells; Cicatrix; Cytometry; Development; Diagnosis; Diagnostic; Dimensions; Drug Delivery Systems; Evaluation; Extravasation; Fluorescence Microscopy; Human; Image; Image Analysis; Imagery; Imaging Techniques; Immune; Immune response; Immunofluorescence Immunologic; Immunohistochemistry; Immunologic Markers; Immunologics; Immunotherapeutic agent; Immunotherapy; Inflammatory Infiltrate; Intervention; Knowledge; Label; Light; Location; Lymphocytic Infiltrate; Malignant Neoplasms; Manuscripts; Maps; Mediating; Methodology; Methods; Microscopy; Microtomy; Modeling; Monitor; Morphologic artifacts; Morphology; Mus; Neurons; Neurosciences; Oncologist; Optics; Organ; Outcome; PDCD1LG1 gene; Pathologist; Patients; Pattern; Penetration; Pharmaceutical Preparations; Population; Protocols documentation; Radiation; Radiation therapy; Research; Residual Tumors; Resolution; Rodent; Sampling; Science; Selection for Treatments; Specimen; Staining method; Stains; Stromal Cells; Structure; Techniques; Therapeutic; Therapeutic antibodies; Thick; Three-Dimensional Imaging; Time; Tissues; Tumor Biology; Tumor Immunity; Tumor Subtype; Tumor Tissue; Uncertainty; base; brain tissue; cancer cell; cancer imaging; cancer immunotherapy; chemotherapy; clinical practice; density; design; drug distribution; effective therapy; fluorescence imaging; high resolution imaging; imaging approach; imaging modality; immune checkpoint; improved; in vivo; in vivo imaging; light microscopy; neoplasm immunotherapy; novel; oncology; outcome forecast; predicting response; prevent; reconstruction; response; spatiotemporal; tomography; tool; treatment response; tumor; tumor growth; tumor immunology; tumor microenvironment; two-dimensional; two-photon

Project Summary This proposal aims to apply an imaging technique for three-dimensional (3D) visualization and mapping of the tumor and microenvironment including cancer cells, stromal cells, immune cells, and vascular cells. The capability to determine the location, density, and functional orientation of different cell populations throughout a tumor would be a powerful tool not only for cancer biology but also for improving diagnosis and advancing the development of effective therapies. Although immunohistochemistry (IHC)/immunofluorescence (IF) staining has long been used in cancer diagnostics, conventional IHC/IF methodology is based on localization of antigens in single thin sections. Considering that most cells in the field of view may be only fragments, interpretation of thin section staining is subject to multiple artifacts. Significantly, IHC/IF may fail to demonstrate important features such as pushing margin, lymphocytic infiltrate, or squamous change, leaving room for diagnostic and therapeutic uncertainties. Recent progress in tissue optical clearing and light microscopy enable 3D fluorescent imaging of normally opaque, thick tissues and organs. Dramatic examples include progress mapping neuronal connectivity in whole rodent brains at subcellular resolution. I sought to adapt these strategies to advance analysis of inflammatory infiltrates, drug delivery, and therapeutic responses in whole mouse tumors and human tumor biopsies. In order to advance 3D tumor imaging, I optimized optical clearing, cell staining, high resolution imaging, and computational reconstruction. Eventually, I developed a 3D tumor imaging method, Transparent Tumor Tomography (T3), as a tool to visualize and map tumors at single cell resolution. In this project, I will apply T3 for spatial analysis of tumor immunology and immunotherapy. T3-mediated 3D tumor imaging will provide integrated spatial information regarding antibody drug distribution and immune contexts in whole tumors which will be useful as a new assay tool for cancer immunotherapy research.

项目摘要 该提案旨在应用成像技术进行三维（3D）可视化和映射， 肿瘤和微环境包括癌细胞、基质细胞、免疫细胞和血管细胞。的 能够确定不同细胞群在整个细胞周期中的位置、密度和功能方向。 肿瘤将不仅是癌症生物学的有力工具，而且也是改善诊断和促进治疗的有力工具。 开发有效的治疗方法。虽然免疫组织化学（IHC）/免疫荧光（IF）染色 尽管已经在癌症诊断中使用了很长时间，但是常规的IHC/IF方法学是基于 单个薄切片中的抗原。考虑到视野中的大多数细胞可能只是碎片， 薄切片染色的解释受到多种假象的影响。重要的是，IHC/IF可能无法证明 重要特征，例如边缘推挤、淋巴细胞浸润或鳞状变化，为肿瘤留下空间 诊断和治疗的不确定性。 组织光学透明和光学显微镜的最新进展使正常组织的3D荧光成像成为可能。 不透明、厚的组织和器官。戏剧性的例子包括整个神经元连接的进展图 啮齿动物大脑的亚细胞分辨率。我试图调整这些策略，以推进炎症的分析， 在整个小鼠肿瘤和人肿瘤活组织检查中的浸润、药物递送和治疗反应。在 为了推进3D肿瘤成像，我优化了光学透明，细胞染色，高分辨率成像， 计算机重建最终，我开发了一种3D肿瘤成像方法，透明肿瘤 断层扫描（T3），作为以单细胞分辨率可视化和映射肿瘤的工具。在这个项目中，我将应用T3 用于肿瘤免疫学和免疫治疗的空间分析。T3介导的3D肿瘤成像将提供 整合了关于抗体药物分布和整个肿瘤中免疫环境的空间信息， 将作为癌症免疫治疗研究的一种新的检测工具。