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A multiplexed microfluidic system for evaluation of dynamics of immune–tumor interactions
Lab on a Chip ( IF 6.1 ) Pub Date : 2018-05-18 00:00:00 , DOI: 10.1039/c8lc00256h
N. Moore 1, 2, 3, 4 , D. Doty 1, 2, 3, 4 , M. Zielstorff 4, 5, 6 , I. Kariv 4, 5, 6 , L. Y. Moy 4, 5, 6 , A. Gimbel 1, 2, 3, 4 , J. R. Chevillet 1, 2, 3, 4 , N. Lowry 1, 2, 3, 4 , J. Santos 1, 2, 3, 4 , V. Mott 1, 2, 3, 4 , L. Kratchman 1, 2, 3, 4 , T. Lau 1, 2, 3, 4 , G. Addona 4, 5, 6 , H. Chen 4, 5, 6 , J. T. Borenstein 1, 2, 3, 4
Affiliation  

Recapitulation of the tumor microenvironment is critical for probing mechanisms involved in cancer, and for evaluating the tumor-killing potential of chemotherapeutic agents, targeted therapies and immunotherapies. Microfluidic devices have emerged as valuable tools for both mechanistic studies and for preclinical evaluation of therapeutic agents, due to their ability to precisely control drug concentrations and gradients of oxygen and other species in a scalable and potentially high throughput manner. Most existing in vitro microfluidic cancer models are comprised of cultured cancer cells embedded in a physiologically relevant matrix, collocated with vascular-like structures. However, the recent emergence of immune checkpoint inhibitors (ICI) as a powerful therapeutic modality against many cancers has created a need for preclinical in vitro models that accommodate interactions between tumors and immune cells, particularly for assessment of unprocessed tumor fragments harvested directly from patient biopsies. Here we report on a microfluidic model, termed EVIDENT (ex vivo immuno-oncology dynamic environment for tumor biopsies), that accommodates up to 12 separate tumor biopsy fragments interacting with flowing tumor-infiltrating lymphocytes (TILs) in a dynamic microenvironment. Flow control is achieved with a single pump in a simple and scalable configuration, and the entire system is constructed using low-sorption materials, addressing two principal concerns with existing microfluidic cancer models. The system sustains tumor fragments for multiple days, and permits real-time, high-resolution imaging of the interaction between autologous TILs and tumor fragments, enabling mapping of TIL-mediated tumor killing and testing of various ICI treatments versus tumor response. Custom image analytic algorithms based on machine learning reported here provide automated and quantitative assessment of experimental results. Initial studies indicate that the system is capable of quantifying temporal levels of TIL infiltration and tumor death, and that the EVIDENT model mimics the known in vivo tumor response to anti-PD-1 ICI treatment of flowing TILs relative to isotype control treatments for syngeneic mouse MC38 tumors.

中文翻译:

用于评估免疫-肿瘤相互作用动力学的多重微流体系统

肿瘤微环境的概述对于探查与癌症有关的机制以及评估化学治疗剂,靶向疗法和免疫疗法对肿瘤的杀灭潜力至关重要。由于微流体装置能够以可扩展且潜在地高通量的方式精确控制药物浓度以及氧气和其他物种的梯度,因此微流体装置已成为用于机理研究和临床前评估的有价值的工具。体外存在最多微流体癌症模型由嵌入生理相关基质中并与血管样结构并置的培养癌细胞组成。但是,最近出现的免疫检查点抑制剂(ICI)作为针对多种癌症的强大治疗手段,因此需要一种临床前体外模型,以适应肿瘤与免疫细胞之间的相互作用,尤其是评估直接从患者活检组织中收获的未加工肿瘤片段的评估。在这里,我们报道了一种称为EVIDENT(离体肿瘤活检的免疫肿瘤动态环境),可在动态微环境中容纳多达12个与流动的肿瘤浸润淋巴细胞(TIL)相互作用的单独的肿瘤活检片段。用一个简单的泵和可扩展的配置即可实现流量控制,并且整个系统使用低吸附性材料构建,解决了现有微流控癌症模型的两个主要问题。该系统可将肿瘤碎片维持多天,并允许对自体TIL和肿瘤碎片之间的相互作用进行实时,高分辨率成像,从而能够绘制TIL介导的肿瘤杀伤图谱并测试各种ICI治疗肿瘤反应。此处报告的基于机器学习的自定义图像分析算法可提供对实验结果的自动和定量评估。初步研究表明,该系统能够量化TIL浸润和肿瘤死亡的时间水平,并且EVIDENT模型模拟了同种小鼠的同种型对照治疗相对于流动TIL的抗PD-1 ICI治疗的已知体内肿瘤反应MC38肿瘤。
更新日期:2018-05-18
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