Tumor microenvironment on-chip model for precision drug discovery in pancreatic cancer

Representing the most common malignancy of the pancreas, pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type. To date, cytotoxic chemotherapy with either gemcitabine or the combination drug FOLFIRINOX represents the first-line-treatment for patients who are ineligible for surgical resection. One factor which contributes to the unfavorable prognosis is the presence of a highly fibrotic and immunosuppressive tumor microenvironment (TME), mainly consisting of cancer associated fibroblasts (CAF) and tumor associated macrophages (TAM). A biochip platform allows the integration of organoids and spheroids. Additionally, it enables the perfusion with primary immune cell population derived from peripheral mononuclear blood cells (PBMC) via an endothelial HUVEC layer under flow conditions. Using this model, we explored the role of the PDAC TME, primarily the role of CAF, on the recruitment and polarization of macrophages. For this, the infiltration of primary monocytes, their differentiation into macrophages and further polarization as well as their influence on spheroid growth and viability in the presence and absence of perfused T cells was analyzed and compared to the localization of TAMs in PDAC patient tumor slices.