Cuenca-Escalona Jorge, Sweep Mark W D, Gorris Mark A J, Duiveman-de Boer Tjitske, Cambi Alessandra, Flórez-Grau Georgina, de Vries Jolanda M
Department of Medical BioSciences, Radboud University Medical Center, Geert Grooteplein 26-28 6500HB, Nijmegen, the Netherlands.
Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10 6525GA, Nijmegen, the Netherlands.
J Leukoc Biol. 2025 May 7;117(5). doi: 10.1093/jleuko/qiaf034.
Dendritic cells (DCs) play a pivotal role in orchestrating adaptive immunity in response to environmental cues such as prostaglandin E2 (PGE2). Tumors are known to establish a microenvironment rich in PGE2. Tumor-derived PGE2 is regarded as mediator of regulatory features in DCs, facilitating immune evasion and tumor progression. In DCs, the effects of PGE2 are mediated through the E-prostanoid receptor type 2 (EP2) and EP4. While the immunomodulatory effects of PGE2 signaling via EP2/4 in monocyte-derived DCs (moDCs) is well established, its role in human blood plasmacytoid DCs (pDCs) is poorly characterized. Therefore, in this study we investigated the effect of EP2 and EP4 signaling on pDC function, as well as the relevance of modulating these receptors in pDCs exposed to tumor-derived PGE2. Our findings reveal that EP2 and EP4 exhibit distinct functions in pDCs. PGE2-EP4 signaling mediates the upregulation of maturation markers (e.g., CD83 and HLA-DR), enhances a CCR7-based migratory function, impairs the production of proinflammatory mediators (e.g., interferon α and CXCL9), and stimulates the expansion of CD8 T cells with a marked suppressive phenotype. In contrast, PGE2-EP2 signaling hinders the upregulation of maturation markers and induces the expansion of CD8 T cells with a suppressive character. Additionally, using different in vitro tumor models, we show that EP2/4 blockade modulates the phenotype of pDCs exposed to tumor-derived PGE2. Together, these results identify the distinctive role of EP2 and EP4 signaling in pDCs and illustrate the potential therapeutic benefit of targeting this signaling axis to mitigate tumor-induced pDCs dysfunction.
树突状细胞（DCs）在响应诸如前列腺素E2（PGE2）等环境信号来协调适应性免疫方面发挥着关键作用。已知肿瘤会建立富含PGE2的微环境。肿瘤来源的PGE2被视为DCs中调节特性的介质，促进免疫逃逸和肿瘤进展。在DCs中，PGE2的作用是通过2型E-前列腺素受体（EP2）和EP4介导的。虽然PGE2通过EP2/4信号通路在单核细胞来源的DCs（moDCs）中的免疫调节作用已得到充分证实，但其在人血浆细胞样DCs（pDCs）中的作用却鲜有报道。因此，在本研究中，我们研究了EP2和EP4信号通路对pDC功能的影响，以及在暴露于肿瘤来源PGE2的pDCs中调节这些受体的相关性。我们的研究结果表明，EP2和EP4在pDCs中表现出不同的功能。PGE2-EP4信号通路介导成熟标志物（如CD83和HLA-DR）的上调，增强基于CCR7的迁移功能，损害促炎介质（如干扰素α和CXCL9）的产生，并刺激具有明显抑制表型的CD8 T细胞的扩增。相反，PGE2-EP2信号通路阻碍成熟标志物的上调，并诱导具有抑制特性的CD8 T细胞的扩增。此外，使用不同的体外肿瘤模型，我们表明EP2/4阻断可调节暴露于肿瘤来源PGE2的pDCs的表型。总之，这些结果确定了EP2和EP4信号通路在pDCs中的独特作用，并说明了靶向该信号轴以减轻肿瘤诱导的pDCs功能障碍的潜在治疗益处。
