Development of organ-on-chip systems for studying the interactions between immune and tumor cells in response to pharmacological treatments

The initiation of an effective anti-cancer immune response critically depends on the dynamic interactions between cancer cells, dendritic cells (DCs), and T lymphocytes. These interactions represent a pivotal step in tumor immune surveillance and remain essential even in the context of therapeutic interventions. Microfluidic-based platforms, such as immune system-cancer-on-a-chip models, have emerged as powerful tools to investigate these processes, as they can faithfully recapitulate key structural and functional features of the tumor microenvironment (TME). Here, we developed an advanced organ-on-a chip (OoC) system to recreate the TME and elucidate the cross-talk between immune and tumor cells. Firstly, we analysed the behaviour into the OoC of monocyte-derived dendritic cells (DCs) and autologous lymphocytes (PBLs) towards sensitive and Vemurafenib (VEM) resistant patient-derived melanoma cells, by testing a new anti-tumor strategy. We observed that the combined treatment of both sensitive and resistant melanoma cells with Tazemetostat, an EZH2 inhibitor, and MSA-2, as STING agonist molecule, induced a marked DCs and PBLs migration towards melanoma cells, with respect to untreated condition, suggesting that the combined treatment can revert the VEM resistance in melanoma. Moreover, to test the versatility of our OoC, we also analysed the behaviour of DCs and PBLs in two different models of breast cancer, moderate and aggressive, elucidating, by means of cell tracking analysis, the different capability to recruit the immune cells into the tumor site. In addition, we integrated the OoC with spheroids derived from HPV16+ cancer cell lines to test the efficacy of anti-E6 treatment to restore the immune cell response against HPV16-related cancer. Overall, our results provide evidence that our OoC represents a versatile and robust system for performing functional assays and testing new anticancer strategies within a single, integrated microfluidic device.