COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

V Prima, LN Kaliberova, S Kaliberov… - Proceedings of the …, 2017 - National Acad Sciences
V Prima, LN Kaliberova, S Kaliberov, DT Curiel, S Kusmartsev
Proceedings of the National Academy of Sciences, 2017National Acad Sciences
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 …
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 E2 (PGE2)-forming enzymes microsomal PGE2 synthase 1 (mPGES1) and COX2. Inhibition of PGE2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.
National Acad Sciences