目的了解前列腺素E2（PGE2）介导的树突状细胞（DC）免疫抑制的机制。在4T1荷瘤小鼠（TBM）上进行体内实验。体外实验是在骨髓来源的 DC（BMDC）或脾细胞中进行的。通过 ELISA/ELIspot 监测细胞因子。通过 RT-PCR/流式细胞术监测基因表达。4T1 TBM 中的计算机、体外和体内实验表明，PGE2 通过 DC 中的 EP4 受体诱导 IL-6/pSTAT3 信号传导，导致其功能障碍。这些效应可被 EP4 抗体中和、EP4 拮抗剂和 STAT3 抑制肽逆转。 PGE2 诱导的 IL-6 可以由 miR-365 调节，因为其模拟物抑制 PGE2 诱导的 IL-6，并且该抑制剂增加 DC 中的 IL-6 水平。人类乳腺癌的生物信息学分析还揭示了 PGE2 和 IL-6 之间较强的相关性（相关性分析 R）（R = 0.94）。携带 PTGS-2 KD 4T1 肿瘤的小鼠肿瘤负荷、PGE2、EP4、IL-6 和 pSTAT3 信号传导减少，同时 DC 和 T 细胞功能得到改善。用环氧合酶-2 (COX-2) 抑制剂或 EP4 拮抗剂治疗小鼠可减轻肿瘤负荷，并且 EP4 拮抗剂的这种作用在体内 CD11c 细胞耗竭后被消除，表明 DC 中 PGE2 信号传导在肿瘤进展中的关键作用。总之，我们的数据强调了树突状细胞在介导 PGE2 介导的免疫抑制和 EP4 或 STAT3 抑制剂中的重要性，或者使用 miR365 模拟物可以恢复癌症中的免疫原性。版权所有 © 2024。由 Elsevier Inc. 出版。

To understand the mechanism of prostaglandin E2 (PGE2)-mediated immunosuppression in dendritic cells (DCs).In vivo experiments were conducted on 4T1 tumor bearing mice (TBM). In vitro experiments were performed in bone marrow-derived DCs (BMDCs), or spleen cells. Cytokines were monitored by ELISA/ELIspot. Gene expression was monitored by RT-PCR/flow cytometry.In silico, in vitro, and in vivo experiments in 4T1 TBM revealed that PGE2 induced IL-6/pSTAT3 signaling through EP4 receptors in DCs, resulting in their dysfunction. These effects were reversed by EP4 antibody neutralization, EP4 antagonist, and STAT3 inhibitory peptides. PGE2 induced IL-6 could be regulated by miR-365, as its mimic inhibited PGE2 induced IL-6 and the inhibitor increased lL-6 levels in DC. Bio-informatic analysis in human mammary cancers also revealed a strong compared co-relation between PGE2 and IL-6 (Correlation AnalyzeR) (R = 0.94). Mice bearing PTGS-2 KD 4T1 tumors had decreased tumor burden, PGE2, EP4, IL-6, and pSTAT3 signaling, along with improved DCs and T cell functions. Treatment of mice with a cyclooxygenase-2 (COX-2) inhibitor or EP4 antagonist decreased tumor burden, and this effect of EP4 antagonist was abrogated upon in vivo depletion of CD11c cells, indicating the crucial role of PGE2 signaling in DCs in tumor progression.In summary, our data highlights the importance of dendritic cells in mediating PGE2-mediated immunosuppression and EP4 or STAT3 inhibitors or the use of miR365 mimics can restore immunogenicity in cancer.Copyright © 2024. Published by Elsevier Inc.