Distinct roles of PGE2 signaling via EP2 and EP4 in circulating pDCs: implications for immune modulation in the tumor microenvironment

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 pro-inflammatory mediators (e.g., IFNα 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 pDC dysfunction.