胰腺导管腺癌（PDA）的预后仍然不佳。 PDA患者的生存率低是由于其早期转移率高和当前治疗方法疗效低，部分原因是其复杂的免疫抑制肿瘤微环境。我们小组和其他人之前的研究表明，肿瘤相关巨噬细胞（TAM）有助于维持 PDA 的免疫抑制。在这里，我们探讨了 Notch 信号传导（免疫反应的关键调节因子）在 PDA 微环境中的作用。我们在人和小鼠胰腺癌的多种免疫细胞类型中鉴定出了 Notch 通路成分。 TAM 是肿瘤微环境中最丰富的免疫细胞群，表达高水平的 Notch 受体，并在肿瘤上皮细胞、内皮细胞和成纤维细胞上表达 JAG1 等同源配体。具有激活的Notch信号传导的TAM表达更高水平的免疫抑制介质，这表明Notch信号传导在PDA微环境内的巨噬细胞极化中发挥作用。在原位 PDA 模型中，骨髓细胞中 Notch 的基因抑制导致肿瘤尺寸减小并减少巨噬细胞浸润。药理学Notch抑制与PD-1阻断相结合导致细胞毒性T细胞浸润增加、肿瘤细胞凋亡和肿瘤尺寸缩小。我们的工作表明巨噬细胞Notch信号传导参与了免疫抑制的建立，并表明针对Notch通路可能会提高PDA患者免疫疗法的疗效。

Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, expressed high levels of Notch receptors, with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells, and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators, suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Genetic inhibition of Notch in myeloid cells led to reduced tumor size and decreased macrophage infiltration in an orthotopic PDA model. Combination of pharmacological Notch inhibition with PD-1 blockade resulted in increased cytotoxic T-cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.