title: COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells.
abstract: 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 PGE2synthase 1 (mPGES1) and COX2. Inhibition of PGE2formation, 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/PGE2pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.
authors.affiliation: Department of Urology, College of Medicine, University of Florida, Gainesville, FL 32610.
authors.forename: Victor
authors.initials: V
authors.lastname: Prima
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: Lyudmila N
authors.initials: LN
authors.lastname: Kaliberova
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kaliberov
authors.affiliation: Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Department of Urology, College of Medicine, University of Florida, Gainesville, FL 32610; sergei.kusmartsev@gmail.com.
authors.forename: Sergei
authors.initials: S
authors.lastname: Kusmartsev
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D011448:Prostaglandin Antagonists; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
keywords: PD-L1; PGE2 metabolism; bone marrow; myeloid cells; tumor-associated macrophages