Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type is estimated to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. PDAC is characterized by high-density stroma and an immunosuppressive tumor microenvironment that lead to a lack of efficacy of immunotherapeutic strategies. Those facts highlight the urgent need for more relevant PDAC in vitro models that support the discovery of novel (immuno-)therapies. Here, we describe the establishment of a multiple cell type culture in a microfluidic platform that will be applied for modeling immune and stroma cell interplay in PDAC.
Microfluidic platforms such as the OrganoPlate® support 3D growth and inclusion of different cell types cultured under flow conditions. The aim of this project was to determine the involvement of stromal cells such as endothelial cells and pancreatic stellate cells in immune cell recruitment in pancreatic cancer. In order to generate a more relevant culture set up, supporting cells and PDAC organoids were used in the 3-lane OrganoPlate® to study immune cell recruitment. Migration of fluorescently labelled peripheral blood mononuclear cells from vasculature through the stromal compartment to the PDAC organoids was tracked for 72h using confocal microscopy.
Migration of immune cells to the tumor cell compartment was significantly inhibited by the stromal compartment, thus confirming in vivo immune responses, as the stroma seems to form both a physical as well as a chemical barrier for immune cells to reach the active tumor site. Interestingly, PDAC organoid conditioned medium efficiently attracts immune cells into the tumor compartment, indicating that secreted factors play a relevant role in immune cell recruitment. Despite the positive effect on recruitment and immune-tumor cell interaction, a lack of tumor cell killing is observed.
The co-culture of PDAC organoids with stromal and immune cells grown on-a-Chip as described in this study indicates the suitability of microfluidic platforms for generating complex models and its use for dissecting complex cellular interplay and processes involved in the lack of anti-tumor immune responses in PDAC.
Mimetas.
European Union.
All authors have declared no conflicts of interest.