Abstract
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.