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

N Obermajer, R Muthuswamy, J Lesnock… - Blood, The Journal …, 2011 - ashpublications.org
N Obermajer, R Muthuswamy, J Lesnock, RP Edwards, P Kalinski
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
Abstract
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.
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