PGE1 Suppresses the Expression of M2 Markers on Macrophages Through Prostaglandin Receptors.

M2-like tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, particularly for cancer patients who are refractory to current immune checkpoint inhibitors (ICIs). Previously, we showed that prostaglandin E1 (PGE1) enhances the expression of M1 markers, including HLA-DR, on macrophages and induces the M1 polarization of TAMs in vivo. This study investigated the pharmacological mechanisms by which PGE1 and its derivatives suppress the expression of M2 markers, including TREM2 and CXCR2. Macrophages were cultured in ultralow attachment dishes either alone or in combination with liver cancer cell lines to generate homospheroids or heterospheroids. Cell surface marker expression was assessed by flow cytometry. Compared with homospheroids, M2 marker expression on macrophages in heterospheroids was significantly increased, suggesting that heterospheroid culture promotes M2 polarization. PGE1 decreased M2 marker expression in heterospheroids more effectively compared with PGE2, PGE3, misoprostol, and 13,14-dihydro-15-keto-PGE1, whereas the suppressive effects of 15-keto- and 13,14-dihydro-PGE1s, and lubiprostone were comparable to that of PGE1. Pharmacological inhibition of prostaglandin receptors revealed that EP2 and EP4 receptors are involved in the PGE1-induced reprogramming of M2-like macrophages to M1 macrophages. In summary, PGE1 and its derivatives are promising TAM-targeting immunotherapeutics.