Acoustic assembly of patient tumor organoids for modeling cancer immunity

用于模拟癌症免疫的患者肿瘤类器官的声学组装

基本信息

批准号：
10041819
负责人：
Feng Guo
金额：
$ 7.93万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10041819
关键词：
3-Dimensional Acoustics Address Blood specimen Breast Cancer Patient Cancer Model Cancer cell line Cell Communication Cell Culture Techniques Cell Line Cells Cellular Structures Coculture Techniques Combined Modality Therapy Development Engineering Immune Immune checkpoint inhibitor Immune system Immunotherapeutic agent In Vitro Infiltration Malignant Neoplasms Methods Microfluidics Modeling Monitor Organoids Outcome Patients Reporting Research Sampling Solid Neoplasm Structure T-Lymphocyte Testing Time Tissue Sample Tumor Immunity Tumor Tissue Variant Work Xenograft procedure cancer cell cancer immunotherapy cancer therapy cell motility cellular imaging chemotherapy clinical predictors cytotoxicity exhaustion falls high throughput screening imaging approach immune checkpoint blockade improved in vivo innovation neoplastic cell novel real-time images response scaffold screening technology development three dimensional cell culture trafficking tumor tumor microenvironment tumor-immune system interactions

3-Dimensional Acoustics Address Blood specimen Breast Cancer Patient Cancer Model Cancer cell line Cell Communication Cell Culture Techniques Cell Line Cells Cellular Structures Coculture Techniques Combined Modality Therapy Development Engineering Immune Immune checkpoint inhibitor Immune system Immunotherapeutic agent In Vitro Infiltration Malignant Neoplasms Methods Microfluidics Modeling Monitor Organoids Outcome Patients Reporting Research Sampling Solid Neoplasm Structure T-Lymphocyte Testing Time Tissue Sample Tumor Immunity Tumor Tissue Variant Work Xenograft procedure cancer cell cancer immunotherapy cancer therapy cell motility cellular imaging chemotherapy clinical predictors cytotoxicity exhaustion falls high throughput screening imaging approach immune checkpoint blockade improved in vivo innovation neoplastic cell novel real-time images response scaffold screening technology development three dimensional cell culture trafficking tumor tumor microenvironment tumor-immune system interactions

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项目摘要

Project Summary Modeling the native dynamic interaction between tumor and immune system is crucial for developing and testing new precision immunotherapeutic strategies, as well as predicting clinical response to innovative cancer treatments, such as immune checkpoint blockade therapy. Tremendous efforts have been focused on the development of current patient-derived cancer models including 2D primary cancer cell cultures, 3D spheroid and organoid cultures, and patient-derived xenografts (PDX). However, these models fall short of reproducing patients’ native cancer-immune interaction dynamics, largely due to their low throughput, lengthy culture periods (several weeks), lack of tumor microenvironmental components (e.g. immune cells), and/or scaffolding that interferes with T cell migration and cellular interaction. Our overall objective here is to acoustically assemble novel patient organoids that represent the microenvironmental components of a patient’s tumor in order to screen immune cell infiltration and cytotoxicity dynamics in a high-throughput and time efficient manner. Our preliminary research demonstrated the acoustic assembly of about 6,000 scaffold-free homotypic tumor spheroids in one day using standard cell lines. The proposed project aims to (1) acoustically assemble a large number of heterotypic organoids using patient tumor samples; (2) monitor the dynamic T cell interaction with acoustically-engineered patient organoids trapped on a pillar array using our microfluidic high throughput, time-lapse single cell imaging approach; and (3) determine T cell tumor dynamic infiltration and cytotoxicity or exhaustion. We expect the proposed work will yield three outcomes. First, a novel acoustic organoid model will be developed to form a high number of heterotypic patient tumor organoids. Second, this platform will be employed to study T cell tumor infiltration dynamics and exhaustion in immunosuppressive microenvironments that closely mimic the patient tumor. Third, this platform will allow high-throughput and high-efficiency screening of agents (e.g. immune checkpoint inhibitors) for the development of novel cancer immunotherapy strategies to treat solid tumors.

项目摘要建模肿瘤与免疫系统之间的天然动态相互作用对于开发和测试至关重要新的精确免疫治疗策略，并预测对创新癌症的临床反应巨大的努力集中在治疗上，例如免疫检查点阻滞治疗。开发当前患者来源的癌症模型，包括2D原发性癌细胞培养物，3D球体和器官培养物以及患者衍生的Xenographictic（PDX）。但是，这些模型没有繁殖患者的天然癌症免疫相互作用动力学，主要是由于其低吞吐量，冗长的培养时间（几周），缺乏肿瘤微环境成分（例如免疫细胞）和/或脚手架与T细胞迁移和细胞相互作用的交流。我们这里的总体目标是准确组装新的患者类器官，代表为了筛选免疫细胞浸润和细胞毒性，患者肿瘤的微环境成分高通量和时间效率的动态。我们的初步研究证明了声学使用标准细胞系在一天内组装约6,000个无脚手型同型肿瘤球体。这拟议的项目的目的是（1）使用患者管来组装大量的异型器官样品；（2）监视与被困在A上的声学设计的患者类型的动态T细胞相互作用使用我们的微流体高通量，延时单细胞成像方法的支柱阵列；（3）确定t 细胞肿瘤动态浸润和细胞毒性或精疲力尽。我们预计拟议的工作将产生三个结果。首先，将开发出一种新型的声学器官模型形成大量的异型患者肿瘤器官。其次，该平台将被雇用来研究细胞肿瘤浸润动力学和精疲力尽患者肿瘤。第三，该平台将允许对代理的高通量和高效率筛查（例如免疫检查点抑制剂）用于开发新型癌症免疫疗法治疗实体瘤的策略。