PGE2-EP4 signaling steers cDC2 maturation towards the induction of suppressive T cell responses.

Dendritic cells (DCs) shape adaptive immunity in response to environmental cues such as cytokines or lipid mediators, including prostaglandin E2 (PGE2). In cancer, tumors are known to establish an enriched PGE2-microenvironment. Tumor-derived PGE2 primes regulatory features across immune cells, including DCs, facilitating tumor progression. PGE2 shapes DC function by providing signaling via its two so-called E-prostanoid receptors (EPs) EP2 and EP4. While studies with monocyte-derived DCs (moDCs) have shown the importance of PGE2 signaling, the role PGE2-EP2/EP4 on conventional DCs type 2 (cDC2s), is still poorly defined. In this study, we investigated the function of EP2 and EP4 using specific EP antagonists on human cDC2s. Our results show that EP2 and EP4 exhibit different functions in cDC2s, with EP4 modulating the upregulation of activation markers (CD80, CD86, CD83, MHC class II) and the production of interleukin 10 (IL-10) and IL-23. Furthermore, PGE2-EP4 boosts CCR type 7 (CCR7) based migration as well as a higher T cell expansion capacity, characterized by the enrichment of suppressive rather than pro-inflammatory T cell populations. Our findings are relevant to further understanding the role of EP receptors in cDC2s, underscoring the benefit of targeting PGE2-EP2/4 axis for therapeutic purposes in diseases such as cancer. This article is protected by copyright. All rights reserved.