Graduate School, Tianjin Medical University, Tianjin, 300070, China.
Institute of Integrated Traditional Chinese and western Medicine, Tianjin Nankai Hospital, Tianjin, 300100, China.
Biomed Pharmacother. 2019 Jul;115:108952. doi: 10.1016/j.biopha.2019.108952. Epub 2019 May 9.
The pancreatic ductal adenocarcinoma (PDAC) microenvironment plays a critical role in the antitumor immune response. 2-arachidonoylglycerol (2-AG) exhibits a direct antitumor effect in various tumor models. However, the immunomodulatory effect of 2-AG on PDAC remains obscure. The aim of this study was to explore the tumor microenvironment response to 2-AG in pancreatic cancer. A PDAC orthotopic tumor model was used to investigate tumor proliferation and the population of immune cells in vivo, including dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), CD8 T cells and CD4 T cells. The effect of 2-AG on panc02 cell proliferation and DC2.4 cell maturation in vitro by mediating activation the typical cannabinoid receptors (CB1, CB2) was evaluated by flow cytometry and CCK8. The protein levels of P-STAT6, STAT6 and GADPH were measured by Western blotting.2-AG inhibited pancreatic cancer cell proliferation in tumor bearing mice and panc02 cell. Inhibition of proliferation was blocked by the CB1receptor antagonist (AM251) but not the CB2 receptor antagonist (AM630). In addition, 2-AG promoted DC phenotypic maturation and the production of proinflammatory cytokines by up-regulating p-STAT6. These effects were also blocked by AM251 but not AM630. Moreover, we also provide evidence that 2-AG administration induced the expansion of MDSCs in tumor bearing mice. However, no effect on the population of CD8 T cells and CD4 T cells was observed. Our findings support 2-AG exhibited direct antitumor effects via inhibiting pancreatic cancer proliferation and inducing DC phenotypic maturation, but also significantly promoted an immunosuppressive microenvironment via increasing the suppressive immune cell population of MDSCs.
胰腺导管腺癌 (PDAC) 微环境在抗肿瘤免疫反应中起着关键作用。2-花生四烯酸甘油 (2-AG) 在各种肿瘤模型中表现出直接的抗肿瘤作用。然而，2-AG 对 PDAC 的免疫调节作用尚不清楚。本研究旨在探讨 2-AG 对胰腺癌肿瘤微环境的影响。使用 PDAC 原位肿瘤模型在体内研究肿瘤增殖和免疫细胞群体，包括树突状细胞 (DCs)、髓系来源的抑制细胞 (MDSCs)、CD8 T 细胞和 CD4 T 细胞。通过流式细胞术和 CCK8 评估 2-AG 通过激活典型大麻素受体 (CB1、CB2) 对 panc02 细胞增殖和 DC2.4 细胞成熟的体外作用。通过 Western blot 测量 P-STAT6、STAT6 和 GADPH 的蛋白水平。2-AG 抑制荷瘤小鼠和 panc02 细胞中的胰腺癌细胞增殖。增殖抑制被 CB1 受体拮抗剂 (AM251) 但不是 CB2 受体拮抗剂 (AM630) 阻断。此外，2-AG 通过上调 p-STAT6 促进 DC 表型成熟和促炎细胞因子的产生。这些作用也被 AM251 但不是 AM630 阻断。此外，我们还提供了证据表明，2-AG 给药诱导荷瘤小鼠中 MDSCs 的扩增。然而，观察到对 CD8 T 细胞和 CD4 T 细胞群体没有影响。我们的研究结果支持 2-AG 通过抑制胰腺癌细胞增殖和诱导 DC 表型成熟来发挥直接抗肿瘤作用，但也通过增加抑制性免疫细胞 MDSCs 的数量显著促进免疫抑制微环境。
