Abstract：
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.
摘要：
虽然已经做出了相当大的努力来开发新的疗法，到目前为止，胰腺癌的治疗进展没有达到患者的预期。这部分是由于缺乏能够解释该肿瘤的异质性及其低免疫原性的预测性体外模型。为了解决这一点，我们建立并表征了由肿瘤细胞组成的胰腺癌的3D球体模型，癌症相关成纤维细胞，和血液来源的单核细胞。后者的命运是从它们招募到肿瘤球体到极化成肿瘤相关巨噬细胞（TAM）样群体，为免疫抑制微环境的形成提供证据。该3D模型很好地再现了TAM的多种作用及其对药物敏感性和细胞迁移的影响。此外，我们观察到由鞘磷脂和维生素E组成的基于脂质的纳米系统可以影响巨噬细胞的表型，导致TAM的特征性标记减少。总体而言，这种优化的三重共培养模型提供了一种有价值的工具,可以为更全面地了解TAM可塑性以及更多的预测性药物筛选找到有用的应用.这可以增加临床前研究的相关性，并帮助确定有效的治疗方法。
