Core D: Pathology and BioImaging

摘要 由医学博士莫里森指导的CORE D(病理学和生物成像核心)将支持这一临床导向 通过提供全面的最先进的肿瘤免疫状态评估计划 微环境(TME)，使用尖端平台进行全面的免疫分析、细胞和组织 分析、成像和图像分析。核心D包括以下目标： 目标1：提供基础设施以收集、处理、注释和存档肿瘤样本并评估 使用全面的免疫图谱分析TME的免疫状态。我们的组织采购处将 帮助从该计划和组织库的临床试验中收集新鲜的、冷冻的和FFPE肿瘤标本 协议。OmniSeq和多重IHC亚核，将执行免疫学、基因组和转录 使用CLIA认证的免疫报告卡™评估TME的免疫状态，以确定： 1)384个免疫基因的转录水平，2)每个肿瘤的突变负担，3)微卫星不稳定性，以及 4)PD-L1和PD-L2的拷贝数增加。我们还将评估治疗中TCR Beta的变化 评估TME中肿瘤特异性T细胞反应的证据和6)表达模式 PD-1/PD-L1/PD-L2系统和COX2系统与T细胞浸润及临床预后的关系 目标2：提供最先进的免疫荧光成像和流式细胞仪服务 趋化因子调节剂对免疫细胞内流、效应和免疫抑制的空间效应 TME中的机制。它将提供最先进的多色血流和成像细胞术，共聚焦激光 扫描和多色荧光显微镜，结合计算机形态测量和图像分析。 目标3(亚核D3)：进行小动物活体成像以确定肿瘤生长的动力学 (生物发光)和CTL在TME中的运输和积累的动力学。 程序性角色和互动。在项目1、2和3中，我们将评估人类的免疫图谱 趋化因子调节治疗结直肠癌、卵巢肿瘤和黑色素瘤的研究 方案和/或DC疫苗；确定CTL和其他的密度、克隆性和分布的变化 CKM对人和小鼠肿瘤免疫细胞的影响 PD-1的阻断作用，并测定差异治疗和未治疗小鼠肿瘤的生长动力学 模特们。我们还将确定治疗对血管正常化和肿瘤形成的影响- 相关淋巴结构与表位扩散和长期治疗效果有关。核心D将 与核心A互动以确定服务的优先顺序，与核心B互动以确保研究和声音的适当设计 对结果进行统计评价。我们将与Core C密切合作，确保所有 临床试验中的样本、样本注释和临床结果评估。

ABSTRACT Core D (Pathology and Bio-Imaging Core), directed by Dr. Morrison, MD, will support this clinically oriented Program by providing comprehensive state-of-the-art evaluation of the immune status of tumor microenvironments (TME), using cutting-edge platforms for comprehensive immune profiling, cell and tissue analysis, imaging and image-analysis. Core D includes the following Aims: Aim 1: Provide infrastructure to collect, process, annotate and archive tumor samples and evaluate the immune status of the TME using comprehensive immune profiling. Our Tissue Procurement Service will help collect fresh, frozen and FFPE tumor specimens from the clinical trials of this Program and tissue banking protocols. OmniSeq and multiplex IHC subcore, will perform immunologic, genomic, and transcriptomic assessment of the immune status of the TME, using CLIA-certified Immune Report Card™ (IRC), to determine: 1) transcript levels of 384 immune genes, 2) mutational burden of each tumor, 3) microsatellite instability, and 4) copy number gain of PD-L1 and PD-L2. We will also evaluate 5) on-treatment changes in TCR beta repertoire, to evaluate evidence of tumor-specific T cell response in the TME and 6) Patterns of expression of PD-1/PD-L1/PD-L2 system and COX2 system in relation to T cell infiltrate and clinical outcomes. Aim 2: Provide state-of-the-art immuno-fluorescence imaging and flow cytometry services to interrogate the spatial effects of chemokine modulating agents on immune cell influx, effector- and immuno-suppressive mechanisms in the TME. It will provide state-of-the-art multicolor flow and imaging cytometry, confocal laser scanning and multicolor fluorescence microscopy, combined with computer morphometry and image analysis. Aim 3 (Sub-Core D3): Perform small animal live imaging to determine the kinetics of tumor growth (bioluminescence) in differentially-treated mice and the kinetics of CTL traffic and accumulation in TME. Programmatic Role and Interactions. With Projects 1, 2 and 3 we will evaluate immune profiles of human colorectal, ovarian and melanoma tumors in the course of patient treatment with chemokine-modulating regimens and/or DC vaccines; determine changes in density, clonality and distribution of CTLs and other immune cells in human and mouse tumors treated by CKM in the absence and presence of vaccination and PD-1 blockade, and determine growth kinetics of the differentially treated and non-treated tumors in murine models. We will also determine the impact of treatments on vascular normalization; and formation of tumor- associated lymphoid structures implicated in epitope spreading and long term-treatment effects. Core D will interact with Core A for prioritization of services, with Core B to assure that proper design of studies and sound statistical evaluation of the results. We will work closely with Core C to ensure failsafe procurement of all specimens from the clinical trials, samples annotation and evaluation in context of clinical outcomes.