COX2/mPGES1/PGE 2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

Significance Programmed cell death protein ligand 1 (PD-L1)–expressing cells mediate tumor evasion from immune system by suppressing activated T lymphocytes. A bioactive lipid prostaglandin E 2 (PGE 2 ) formed from arachidonic acid by COXs and PGE 2 synthases (PGESs) facilitates both cancer inflammation and immune suppression. Here, we show that tumor cells can induce PD-L1 expression in bone marrow–derived cells by affecting PGE 2 metabolism in hematopoietic cells. The tumor-induced PD-L1 expression was limited to the myeloid cell lineage and, specifically, to the macrophages and myeloid-derived suppressor cells. Collectively, the obtained results demonstrate that selective inhibition of PGE 2 -forming enzymes COX2, murine PGES1, or genetic overexpression of PGE 2 -degrading enzyme 15-hydroxyprostaglandin dehydrogenase could provide a novel approach to regulate both PGE 2 levels and PD-L1 expression in cancer, thus alleviating the immune suppression and stimulating antitumor immune response.