Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells

• Published in: Blood Vol. 118; no. 20; pp. 5498 - 5505
• Main Authors: Obermajer, Nataša, Muthuswamy, Ravikumar, Lesnock, Jamie, Edwards, Robert P., Kalinski, Pawel
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 17.11.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Antigens, CD - metabolism; Antigens, CD34 - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Ascites - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cyclooxygenase 2 - metabolism; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dinoprostone - metabolism; Feedback, Physiological - physiology; Female; Hematologic and hematopoietic diseases; Humans; Immunobiology; Immunotherapy - methods; Lipopolysaccharide Receptors - metabolism; Medical sciences; Myeloid Cells - cytology; Myeloid Cells - immunology; Myeloid Cells - metabolism; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Sialic Acid Binding Ig-like Lectin 3; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; Human; Dendritic cell; Prostaglandin-endoperoxide synthase; Hematology; Myeloid derived suppressor cell; Enzyme; Arachidonic acid derivatives; Prostaglandin E2; Cell differentiation; Feedback; Antigen presenting cell; Eicosanoid; Oxidoreductases
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-365825

Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2), the key regulator of PGE2 synthesis, represents the determining factor in redirecting the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs. Exogenous PGE2 and such diverse COX2 activators as lipopolysaccharide, IL-1β, and IFNγ all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs and inducing endogenous PGE2, IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE2 to GM-CSF/IL-4–supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)–suppressive function. In accordance with the key role of PGE2 in the physiologic induction of human MDSCs, the frequencies of CD11b+CD33+ MDSCs in ovarian cancer are closely correlated with local PGE2 production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE2 feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation.