细胞毒性T细胞
嵌合抗原受体
细胞生物学
细胞
肿瘤微环境
癌症研究
癌细胞
卵巢癌
T细胞
生物
细胞外基质
免疫系统
免疫学
癌症
化学
体外
遗传学
生物化学
作者
Joash D. Joy,Beatrice Malacrida,Florian Laforêts,Panoraia Kotantaki,Eleni Maniati,Ranjit Manchanda,Alessandro Annibaldi,Sarah Hopkins,Ianire Garrobo-Calleja,Julien E. Gautrot,Frances R. Balkwill
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-05-31
标识
DOI:10.1158/0008-5472.can-23-3007
摘要
Abstract In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment (TME). Here, we describe the modulation of CAR T cell activity by malignant cells and fibroblasts in human 3D in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer (HGSOC) cell spheroids, malignant cell-intrinsic resistance to CAR T cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell-cell and cell-matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors.
科研通智能强力驱动
Strongly Powered by AbleSci AI