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

Blood. 2011 Nov 17;118(20):5498-505. doi: 10.1182/blood-2011-07-365825. Epub 2011 Oct 4.

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 E(2) (PGE(2)) and cyclooxygenase 2 (COX2), the key regulator of PGE(2) synthesis, represents the determining factor in redirecting the development of CD1a(+) DCs to CD14(+)CD33(+)CD34(+) monocytic MDSCs. Exogenous PGE(2) 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 PGE(2), IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE(2) 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 PGE(2) in the physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in ovarian cancer are closely correlated with local PGE(2) production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE(2) 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-PGE(2) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, CD34 / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Ascites / immunology
  • 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
  • Humans
  • Immunotherapy / methods
  • Lipopolysaccharide Receptors / metabolism
  • 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

Substances

  • Antigens, CD
  • Antigens, CD34
  • Antigens, Differentiation, Myelomonocytic
  • CD33 protein, human
  • Lipopolysaccharide Receptors
  • PTGER2 protein, human
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Sialic Acid Binding Ig-like Lectin 3
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone