Pfirrmann Maren, Bödder Johanna, Wuestenenk Rowan, Tennebroek Jesse, Lyer Kirti K, Poel Dennis, Tauriello Daniele V F, Verdoes Martijn, de Vries I Jolanda M
Department of Medical Biosciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Eur J Immunol. 2025 Nov;55(11):e70090. doi: 10.1002/eji.70090.
Prostaglandin E2 (PGE2) is one important immunosuppressive factor within the tumor microenvironment (TME). Signaling through E-prostanoid receptor type 2 (EP2) and EP4, PGE2 promotes suppressive immune cell phenotypes and impairs antitumor immunity. Blocking PGE2 signaling with EP2 and EP4 antagonists is explored to counteract tumor-induced immunosuppression. While tumor-derived PGE2 is known to modulate human myeloid cell subsets, its specific effects on macrophages remain poorly defined. While murine models show PGE2 induces a protumorigenic macrophage phenotype, the role of PGE2-EP2/4 signaling on human macrophages is unclear. This study evaluates the impact of PGE2 on human macrophage phenotype and function, and the effectiveness of targeting EP2 and EP4 with soluble and nanoparticle-encapsulated antagonists. We show that PGE2 exposure during differentiation of monocytes to macrophages induces a distinct phenotype and affects macrophage functions. Tumor-derived PGE2 predominantly signals through EP2; however, dual blockade of EP2 and EP4 more effectively counteracts PGE2-induced changes. Notably, encapsulation of EP2/4 antagonists enhances the blockade of tumor-derived PGE2 signaling on the macrophage phenotype and their ability to modulate T cell proliferation within patient-derived tumor organoids. These findings underscore the influence of tumor-derived PGE2 on human macrophages and support targeting the PGE2-EP2/4 axis in cancer treatment.
前列腺素E2（PGE2）是肿瘤微环境（TME）中一种重要的免疫抑制因子。通过前列腺素E受体2型（EP2）和EP4发出信号，PGE2可促进免疫抑制细胞表型并损害抗肿瘤免疫力。人们正在探索用EP2和EP4拮抗剂阻断PGE2信号传导，以对抗肿瘤诱导的免疫抑制。虽然已知肿瘤来源的PGE2可调节人类髓细胞亚群，但其对巨噬细胞的具体作用仍不清楚。虽然小鼠模型显示PGE2可诱导促肿瘤巨噬细胞表型，但PGE2-EP2/4信号传导对人类巨噬细胞的作用尚不清楚。本研究评估了PGE2对人类巨噬细胞表型和功能的影响，以及用可溶性和纳米颗粒包裹的拮抗剂靶向EP2和EP4的有效性。我们发现，单核细胞分化为巨噬细胞过程中暴露于PGE2会诱导出一种独特的表型并影响巨噬细胞功能。肿瘤来源的PGE2主要通过EP2发出信号；然而，对EP2和EP4的双重阻断能更有效地抵消PGE2诱导的变化。值得注意的是，EP2/4拮抗剂的包裹增强了对肿瘤来源的PGE2信号传导对巨噬细胞表型的阻断作用，以及它们调节患者来源的肿瘤类器官内T细胞增殖的能力。这些发现强调了肿瘤来源的PGE2对人类巨噬细胞的影响，并支持在癌症治疗中靶向PGE2-EP2/4轴。
