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Abstract
Immunotherapy efficacy relies on the crosstalk within the tumor microenvironment between cancer and dendritic cells (DCs) resulting in the induction of a potent and effective antitumor response. DCs have the specific role of recognizing cancer cells, taking up tumor antigens (Ags) and then migrating to lymph nodes for Ag (cross)-presentation to naïve T cells. Interferon-α-conditioned DCs (IFN-DCs) exhibit marked phagocytic activity and the special ability of inducing Ag-specific T-cell response. Here, we have developed a novel microfluidic platform recreating tightly interconnected cancer and immune systems with specific 3D environmental properties, for tracking human DC behaviour toward tumor cells. By combining our microfluidic platform with advanced microscopy and a revised cell tracking analysis algorithm, it was possible to evaluate the guided efficient motion of IFN-DCs toward drug-treated cancer cells and the succeeding phagocytosis events. Overall, this platform allowed the dissection of IFN-DC-cancer cell interactions within 3D tumor spaces, with the discovery of major underlying factors such as CXCR4 involvement and underscored its potential as an innovative tool to assess the efficacy of immunotherapeutic approaches.
Highlights
Immunotherapy efficacy relies on the crosstalk within the tumor microenvironment between cancer and dendritic cells (DCs) resulting in the induction of a potent and effective antitumor response
Based on our previous data showing the ability of R and I (RI) to promote DC recognition of cancer cells[8], we evaluated the phagocytic capacity of Interferon-α-conditioned DCs (IFN-DCs) toward SW620 cells pre-exposed to RI (RI SW620) for 48 h
We found that RI treatment markedly induced both early and late apoptosis in SW620 cells that in turn were phagocytosed at a higher rate by the IFN-DCs as compared to untreated cancer cells (NT SW620) (Fig. 1b,c)
Summary
Immunotherapy efficacy relies on the crosstalk within the tumor microenvironment between cancer and dendritic cells (DCs) resulting in the induction of a potent and effective antitumor response. The recent advances in both cell biology and microengineering have allowed the development of the innovative organ-on-chip approach, which is able to recapitulate in vivo biological microenvironments suitable for studying complex functions, such as cell-cell interactions and dynamic drug stimuli[18, 19] This enormous potential relies first on the recreation of complex 3D spaces characterized by both physical and biochemical cues closely mimicking the in vivo microenvironments[20]. The coordinated integration of a microfluidic assay, advanced microscopy and computational modelling enables the observation of single events as part of the complex biological processes leading to define the physiopathological responses[22, 23] These breakthrough innovations have allowed the study of cancer-immune interactions as well as immunotherapeutic treatments using microfluidic platforms[24]. During dynamic migration, largely guided by the CXCR4/CCL12 axis, IFN-DCs were found to modify their motion in order to interact with drug-treated cancer cells and to take up tumor Ags
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