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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：
10187568
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/10187568
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 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 patient derived xenograft model real-time images response scaffold screening technology development three dimensional cell culture trafficking tumor tumor microenvironment tumor-immune system interactions

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.

项目摘要对肿瘤和免疫系统之间的天然动态相互作用进行建模对于开发和测试至关重要新的精确免疫治疗策略以及预测对创新癌症的临床反应治疗，如免疫检查点阻断疗法。巨大的努力一直集中在目前病人来源的癌症模型的发展，包括2D原代癌细胞培养，3D球体和器官培养，以及患者来源的异种移植(PDX)。然而，这些模型不能再现患者的天然癌症-免疫相互作用动态，主要是由于他们的低吞吐量，漫长的培养周期 (几周)，缺乏肿瘤微环境成分(例如免疫细胞)，和/或支架干扰T细胞迁移和细胞相互作用。我们在这里的总体目标是声学地组装新的患者器官，代表患者肿瘤的微环境成分，以筛选免疫细胞渗透和细胞毒性以高吞吐量和省时的方式进行动态调整。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个无支架的同型肿瘤球体。这个提出的项目的目标是(1)利用患者肿瘤声学组装大量异型有机化合物样本；(2)监测动态T细胞与声学工程患者器官的相互作用使用我们的微流控高通量、延时单细胞成像方法的柱状阵列；以及(3)确定T 肿瘤细胞的动态浸润和细胞毒性或耗竭。我们预计拟议的工作将产生三个结果。首先，将开发一种新的声学有机体模型以形成大量的异型患者肿瘤器质。其次，将利用该平台来研究T 免疫抑制微环境中细胞肿瘤的侵袭动力学和耗竭病人肿瘤。第三，该平台将允许高通量和高效率地筛选代理(例如免疫检查点抑制剂)，用于开发治疗实体瘤的新的癌症免疫治疗策略。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Controllable fusion of human brain organoids using acoustofluidics.

DOI：
10.1039/d0lc01141j
发表时间：
2021-02-23
期刊：
Lab on a chip
影响因子：
6.1
作者：
Ao Z;Cai H;Wu Z;Ott J;Wang H;Mackie K;Guo F
通讯作者：
Guo F

Tubular human brain organoids to model microglia-mediated neuroinflammation.

DOI：
10.1039/d1lc00030f
发表时间：
2021-07-13
期刊：
Lab on a chip
影响因子：
6.1
作者：
Ao Z;Cai H;Wu Z;Song S;Karahan H;Kim B;Lu HC;Kim J;Mackie K;Guo F
通讯作者：
Guo F

Acoustofluidic assembly of primary tumor-derived organotypic cell clusters for rapid evaluation of cancer immunotherapy.

原发性肿瘤衍生的器官细胞簇的大声组装，用于快速评估癌症免疫疗法。

DOI：
10.1186/s12951-023-01786-6
发表时间：
2023-02-04
期刊：
JOURNAL OF NANOBIOTECHNOLOGY
影响因子：
10.2
作者：
Wu, Zhuhao;Ao, Zheng;Cai, Hongwei;Li, Xiang;Chen, Bin;Tu, Honglei;Wang, Yijie;Lu, Rongze Olivia;Gu, Mingxia;Cheng, Liang;Lu, Xin;Guo, Feng
通讯作者：
Guo, Feng

Rapid Profiling of Tumor-Immune Interaction Using Acoustically Assembled Patient-Derived Cell Clusters.

DOI：
10.1002/advs.202201478
发表时间：
2022-08
期刊：
ADVANCED SCIENCE
影响因子：
15.1
作者：
Ao, Zheng;Wu, Zhuhao;Cai, Hongwei;Hu, Liya;Li, Xiang;Kaurich, Connor;Chang, Jackson;Gu, Mingxia;Liang, Cheng;Lu, Xin;Guo, Feng
通讯作者：
Guo, Feng

Understanding Immune-Driven Brain Aging by Human Brain Organoid Microphysiological Analysis Platform.

DOI：
10.1002/advs.202200475
发表时间：
2022-09
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
0
作者：
Ao Z;Song S;Tian C;Cai H;Li X;Miao Y;Wu Z;Krzesniak J;Ning B;Gu M;Lee LP;Guo F
通讯作者：
Guo F