PDF(Pubmed)
Abstract：
Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.
摘要：
胰腺癌是一种非常侵袭性的疾病，预后不佳。肿瘤微环境通过分泌多种细胞因子发挥免疫抑制活性,包括白细胞介素（IL）-1。IL-1/IL-1受体（IL-1R）轴是肿瘤促进T辅助（Th）2-和Th17型炎症的关键调节因子。Th2细胞通过由IL-1激活的癌症相关成纤维细胞（CAF）分泌的胸腺基质淋巴细胞生成素（TSLP）被赋予Th2极化能力的树突状细胞分化。Thl7细胞在IL-1和其他IL-1调节的细胞因子存在下分化。在胰腺癌中，使用重组IL-1R拮抗剂(IL1RA，anakinra,ANK）在体外和体内模型中已显示出靶向IL-1/IL-1R途径的功效。在这项研究中,我们已经开发了负载ANK的鞘磷脂纳米系统（SNs）（ANK-SNs），以比较它们在体外抑制Th2-和Th17型炎症的能力与游离药物的能力。我们发现ANK-SNs以与ANK相似的水平抑制TSLP和CAF释放的其他促肿瘤细胞因子。重要的是,抑制Th17细胞分泌IL-17，但不是干扰素-γ，明显更高，在较低的浓度下，ANK-SNs与ANK相比。总的来说，使用ANK-SNs可能有利于减少药物的有效剂量及其毒性作用.
