Dissecting Effects of Anti-cancer Drugs and Cancer-Associated Fibroblasts by On-Chip Reconstitution of Immunocompetent Tumor Microenvironments
Marie Nguyen,
Adele De Ninno,
Arianna Mencattini,
Fanny Mermet-Meillon,
Giulia Fornabaio,
Sophia S. Evans,
Mélissande Cossutta,
Yasmine Khira,
Weijing Han,
Philémon Sirven,
Floriane Pelon,
Davide Di Giuseppe,
Francesca Romana Bertani,
Annamaria Gerardino,
Ayako Yamada,
Stéphanie Descroix,
Vassili Soumelis,
Fatima Mechta-Grigoriou,
Gérard Zalcman,
Jacques Camonis,
Eugenio Martinelli,
Luca Businaro,
Maria Carla Parrini
Affiliations
Marie Nguyen
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Adele De Ninno
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
Arianna Mencattini
Department of Electronic Engineering, University of Rome Tor Vergata, 00133 Rome, Italy
Fanny Mermet-Meillon
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Giulia Fornabaio
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Sophia S. Evans
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Mélissande Cossutta
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Yasmine Khira
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Weijing Han
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Philémon Sirven
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
Floriane Pelon
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
Davide Di Giuseppe
Department of Electronic Engineering, University of Rome Tor Vergata, 00133 Rome, Italy
Francesca Romana Bertani
Institute for Photonics and Nanotechnology, Italian National Research Council, 00156 Rome, Italy
Annamaria Gerardino
Institute for Photonics and Nanotechnology, Italian National Research Council, 00156 Rome, Italy
Ayako Yamada
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
Stéphanie Descroix
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
Vassili Soumelis
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
Fatima Mechta-Grigoriou
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
Gérard Zalcman
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
Jacques Camonis
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France
Eugenio Martinelli
Department of Electronic Engineering, University of Rome Tor Vergata, 00133 Rome, Italy
Luca Businaro
Institute for Photonics and Nanotechnology, Italian National Research Council, 00156 Rome, Italy
Maria Carla Parrini
Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005 Paris, France; ART Group, INSERM U830, 75005 Paris, France; Corresponding author
Summary: 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. : Inspired by the emerging technology of tumor-on-chip, Nguyen et al. reconstituted ex vivo a human tumor microenvironment (HER2+ breast cancer), characterized the ecosystem-level responses to the drug trastuzumab (Herceptin), and dissected the roles of stromal components (immune cells and fibroblasts), demonstrating the power of immunocompetent tumors-on-chip for preclinical drug studies. Keywords: tumor microenvironment, organ-on-chip, tumor-on-chip, trastuzumab, HER2+ breast cancer, cancer-associated fibroblasts, live cell imaging, microfluidics, pre-clinical models, immunotherapy
