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Cell Rep. 2018 Dec 26;25(13):3884-3893.e3. doi: 10.1016/j.celrep.2018.12.015.

Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments.

Author information

1
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France.
2
Institute for Photonics and Nanotechnology, Italian National Research Council, 00156 Rome, Italy; Department of Civil Engineering and Computer Science, University of Rome Tor Vergata, 00133 Rome, Italy.
3
Department of Electronic Engineering, University of Rome Tor Vergata, 00133 Rome, Italy.
4
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; Immunity and Cancer, INSERM U932, INSERM Center of Clinical Investigations, CIC IGR Curie, 75005 Paris, France.
5
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; Stress and Cancer Team, labelized by Ligue Nationale Contre le Cancer, INSERM U830, 75005 Paris, France.
6
Institute for Photonics and Nanotechnology, Italian National Research Council, 00156 Rome, Italy.
7
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; Laboratoire Physico Chimie Curie, CNRS UMR168, 75005 Paris, France; Institut Pierre-Gilles de Gennes, 75005 Paris, France.
8
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France; Centre d'Investigation Clinique (CIC) 1425, Hôpital Bichat-Claude Bernard, Université Paris-Diderot, Paris, France.
9
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France. Electronic address: maria-carla.parrini@curie.fr.

Abstract

A major challenge in cancer research is the complexity of the tumor microenvironment, which includes the host immunological setting. Inspired by the emerging technology of organ-on-chip, we achieved 3D co-cultures in microfluidic devices (integrating four cell populations: cancer, immune, endothelial, and fibroblasts) to reconstitute ex vivo a human tumor ecosystem (HER2+ breast cancer). We visualized and quantified the complex dynamics of this tumor-on-chip, in the absence or in the presence of the drug trastuzumab (Herceptin), a targeted antibody therapy directed against the HER2 receptor. We uncovered the capacity of the drug trastuzumab to specifically promote long cancer-immune interactions (>50 min), recapitulating an anti-tumoral ADCC (antibody-dependent cell-mediated cytotoxicity) immune response. Cancer-associated fibroblasts (CAFs) antagonized the effects of trastuzumab. These observations constitute a proof of concept that tumors-on-chip are powerful platforms to study ex vivo immunocompetent tumor microenvironments, to characterize ecosystem-level drug responses, and to dissect the roles of stromal components.

KEYWORDS:

HER2(+) breast cancer; cancer-associated fibroblasts; immunotherapy; live cell imaging; microfluidics; organ-on-chip; pre-clinical models; trastuzumab; tumor microenvironment; tumor-on-chip

PMID:
30590056
DOI:
10.1016/j.celrep.2018.12.015
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