Dissecting Effects of Anti-cancer Drugs and of Cancer-associated Fibroblasts by On-chip Reconstitution of Immunocompetent Tumor Microenvironments

Abstract

A major challenge in cancer research is the complexity of the tumor microenvironment and the necessity to take into account the host immunological setting. An innovative way to address these problems is to exploit the emerging technology of organ-on-chip to achieve co-cultures in microfluidic devises that recapitulate ex vivo the tumor ecosystem. We generated tumors-on-chip integrating four cell populations (cancer, immune, endothelial cells and fibroblasts) in a 3D collagen matrix, reconstituting HER2 breast cancer ecosystem. By time-lapse microscopy, differential live staining and a novel automated analysis method, we visualized, and quantified the complex dynamics of this ecosystem, in absence or in 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 (≳ 60 min), recapitulating an anti-tumoral ADCC (antibody-dependent cell-mediated cytotoxicity) immune response. Cancer-associated fibroblasts (CAFs) on the contrary inhibited cancer-immune interactions, antagonizing the action of the trastuzumab. These observations constitute a proof-of-concept that tumors-on-chip are novel powerful platforms that can be exploited to study ex vivo immunocompetent tumor microenvironments, to characterize ecosystem-level responses to anti-cancer drugs, and to dissect the roles of the various cellular components of the stroma.