具有3D内皮的肺肿瘤微物理系统,用于评估T细胞迁移的调节剂。

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 Epub Date: 2023-06-16 DOI:10.14573/altex.2208121
Katrina M Wisdom, Johnny Suijker, Lenie Van den Broek, BanuPriya Sridharan, Taraka Sai Pavan Grandhi, Aaron Cheng, Mahdi Lamb, Steven A Titus, Derek Poore, Niyant Shah, Shih-Hsun Cheng, Edward Kim, Suzanne Griffin, Jason Ekert
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引用次数: 0

摘要

癌症是全球死亡的主要原因,只有一小部分患者对免疫疗法有反应。T细胞浸润增加与阳性患者结果之间的相关性促使人们寻找促进T细胞浸润的治疗方法。虽然已经使用了transwell和球体平台,但这些模型缺乏流动和内皮屏障,并且不能忠实地模拟T细胞通过3D组织的粘附、外渗和迁移。本文介绍了一种在具有3D内皮的肺肿瘤芯片模型(LToC Endo)中进行的3D趋化性测定,以满足这一需求。所述测定由在摇摆流下培养的HUVEC衍生的血管小管组成,通过该血管小管添加T细胞;胶原基质屏障,T细胞通过该屏障迁移;和化学引诱剂/肿瘤(HCC0827或NCI-H520)隔室。在这里,活化的T细胞外渗并迁移以响应rhCXCL11和rhCXCL12的梯度。采用具有休息期的T细胞激活方案可以在将T细胞引入芯片之前实现增殖爆发,并提高检测灵敏度。此外,结合此剩余物可恢复对rhCXCL12的内皮激活。作为最后的对照,我们发现阻断ICAM-1会干扰T细胞的粘附和趋化性。该微物理系统模拟体内基质和血管屏障,可用于评估免疫趋化性对肿瘤的增强作用,同时探索血管对潜在治疗方法的反应。最后,我们提出了转化策略,通过该策略,该测定可以与临床前和临床模型联系起来,以支持人类剂量预测、个性化药物以及动物模型的减少、改进和替换。
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Lung tumor microphysiological system with 3D endothelium to evaluate modulators of T-cell migration.

Lung cancer is a leading cause of death worldwide, with only a fraction of patients responding to immunotherapy. The correlation between increased T-cell infiltration and positive patient outcomes has motivated the search for therapeutics promoting T-cell infiltration. While transwell and spheroid platforms have been employed, these models lack flow and endothelial barriers, and cannot faithfully model T-cell adhesion, extravasation, and migration through 3D tissue. Presented here is a 3D chemotaxis assay, in a lung tumor-on-chip model with 3D endothelium (LToC-Endo), to address this need. The described assay consists of a HUVEC-derived vascular tubule cultured under rocking flow, through which T-cells are added; a collagenous stromal barrier, through which T-cells migrate; and a chemoattractant/tumor (HCC0827 or NCI-H520) compartment. Here, activated T-cells extravasate and migrate in response to gradients of rhCXCL11 and rhCXCL12. Adopting a T-cell activation protocol with a rest period enables proliferative burst prior to introducing T-cells into chips and enhances assay sensitivity. In addition, incorporating this rest recovers endothelial activation in response to rhCXCL12. As a final control, we show that blocking ICAM-1 interferes with T-cell adhesion and chemotaxis. This microphysiological system, which mimics in vivo stromal and vascular barriers, can be used to evaluate potentiation of immune chemotaxis into tumors while probing for vascular responses to potential therapeutics. Finally, we propose translational strategies by which this assay could be linked to preclinical and clinical models to support human dose prediction, personalized medicine, and the reduction, refinement, and replacement of animal models.

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来源期刊
Altex-Alternatives To Animal Experimentation
Altex-Alternatives To Animal Experimentation MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
7.70
自引率
8.90%
发文量
89
审稿时长
2 months
期刊介绍: ALTEX publishes original articles, short communications, reviews, as well as news and comments and meeting reports. Manuscripts submitted to ALTEX are evaluated by two expert reviewers. The evaluation takes into account the scientific merit of a manuscript and its contribution to animal welfare and the 3R principle.
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