Multicellular tumor spheroid model to study the multifaceted role of tumor-associated macrophages in PDAC.

While considerable efforts have been made to develop new therapies, progress in the treatment of pancreatic cancer has so far fallen short of patients' expectations. This is due in part to the lack of predictive in vitro models capable of accounting for the heterogeneity of this tumor and its low immunogenicity. To address this point, we have established and characterized a 3D spheroid model of pancreatic cancer composed of tumor cells, cancer-associated fibroblasts, and blood-derived monocytes. The fate of the latter has been followed from their recruitment into the tumor spheroid to their polarization into a tumor-associated macrophage (TAM)-like population, providing evidence for the formation of an immunosuppressive microenvironment.This 3D model well reproduced the multiple roles of TAMs and their influence on drug sensitivity and cell migration. Furthermore, we observed that lipid-based nanosystems consisting of sphingomyelin and vitamin E could affect the phenotype of macrophages, causing a reduction of characteristic markers of TAMs. Overall, this optimized triple coculture model gives a valuable tool that could find useful application for a more comprehensive understanding of TAM plasticity as well as for more predictive drug screening. This could increase the relevance of preclinical studies and help identify effective treatments.