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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-01, Vol.114 (5), p.1117-1122
• Main Authors: Prima, Victor, Kaliberova, Lyudmila N., Kaliberov, Sergey, Curiel, David T., Kusmartsev, Sergei
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1612920114

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. In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)–mediated inhibition of activated PD-1 + T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti–PD-L1 and –PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow–derived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80 + macrophages and Ly-6C + myeloid-derived suppressor cells. These PD-L1–expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1 + cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E 2 (PGE 2 )-forming enzymes microsomal PGE 2 synthase 1 (mPGES1) and COX2. Inhibition of PGE 2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE 2 -degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE 2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE 2 metabolism in tumo