Abstract 1209: A novel vascularized tumor-on-a-chip model for tracking melanoma-dendritic cell interactions following combined romidepsin and type I IFN therapy

Abstract Dendritic cells (DCs) are key players in melanoma immune surveillance, presenting tumor antigens to CD8+ T cells that target tumor cells. However, the interaction between DCs and tumor cells in the melanoma microenvironment is complex, shaped by tissue structures like endothelial vessels and dynamic biological, chemical, and physical factors. The immunosuppressive tumor microenvironment (TME) often hinders DC migration and their ability to initiate an effective anti-tumor response. Combining romidepsin, an epigenetic agent, with type I interferon (IFN), known to enhance DC function and counteract immune suppression, could enhance DC recruitment to the TME, improve tumor-DC interactions, and boost the anti-tumor immune response. Given the complex interactions between melanoma cells and DCs in the TME, organ-on-chip platforms provide a powerful, human-relevant tool for modeling these dynamics and enabling real-time studies of immune responses to drug treatments.In this study, we developed an innovative tumor-on-a-chip device, designed to closely mimic the human TME. The device features a microvascular structure with a fully integrated lumen, lined by endothelial cells that form tight intercellular junctions, ensuring proper barrier functionality. This engineered setup creates a highly physiologically relevant model of tumor growth at the interface of a flow-perfused blood vessel, offering a 3D environment that mimics the spatial, biochemical, and physical conditions found in vivo. Using this model, we concentrated on examining the migration of DCs through the endothelial barrier, a key process in immune response to tumorigenesis, allowing them to reach and interact with melanoma cells. By applying therapeutic treatments to the system, we demonstrated that DCs exhibit enhanced directional migration toward drug-treated versus untreated metastatic melanoma, likely driven by changes in the TME that promote immune cell trafficking. Furthermore, we report the occurrence of persistent interactions between DCs and drug-treated melanoma cells. These sustained interactions drive continuous DC activation, enhancing their ability to present tumor antigens to T cells and fostering a more robust and lasting anti-tumor immune response. Our findings demonstrate that our novel vascularized tumor-on-a-chip is a powerful tool for studying DC transmigration and tumor cell interactions. This model reveals how therapies influence immune cell dynamics in the TME and offers valuable insights into immune cell trafficking, aiding cancer immunotherapy strategies. Citation Format: Lucia Gabriele, Stefania Parlato, Giulia Silvani, Giovanna Peruzzi, Davide Caprini, Giorgia Sinibaldi, Stefania Rossi, Alesandra Fragale, Giulia Romagnoli, Irene Canini, Arianna Mencattini, Eugenio martinelli, Carlo Massimo Casciola. A novel vascularized tumor-on-a-chip model for tracking melanoma-dendritic cell interactions following combined romidepsin and type I IFN therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1209.