Pivotal Advance: Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE₂ catabolism in myeloid cells

J Leukoc Biol. 2010 Nov;88(5):839-48. doi: 10.1189/jlb.1209821. Epub 2010 Jun 29.

Abstract

Recent studies suggest that tumor-infiltrated myeloid cells frequently up-regulate COX-2 expression and have enhanced PGE₂ metabolism. This may affect the maturation and immune function of tumor-infiltrated antigen-presenting cells. In vitro studies demonstrate that tumor-derived factors can skew GM-CSF-driven differentiation of T(h)1-oriented myeloid APCs into M2-oriented Ly6C(+)F4/80(+) MDSCs or Ly6C(-)F4/80(+) arginase-expressing macrophages. These changes enable myeloid cells to produce substantial amounts of IL-10, VEGF, and MIP-2. The tumor-mediated inhibition of APC differentiation was associated with the up-regulated expression of PGE₂-forming enzymes COX-2, mPGES1 in myeloid cells, and the simultaneous repression of PGE(2)-catabolizing enzyme 15-PGDH. The presence of tumor-derived factors also led to a reduced expression of PGT but promoted the up-regulation of MRP4, which works as a PGE₂ efflux receptor. Addition of COX-2 inhibitor to the BM cell cultures could prevent the tumor-induced skewing of myeloid cell differentiation, partially restoring cell phenotype and down-regulating the arginase expression in the myeloid APCs. Our study suggests that tumors impair the intracellular PGE(2) catabolism in myeloid cells through simultaneous stimulation of PGE(2)-forming enzymes and inhibition of PGE₂-degrading systems. This tumor-induced dichotomy drives the development of M2-oriented, arginase-expressing macrophages or the MDSC, which can be seen frequently among tumor-infiltrated myeloid cells.

MeSH terms

  • Animals
  • Arginase / metabolism
  • Bone Marrow Cells / physiology
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Cytokines / metabolism
  • Dinoprostone / metabolism*
  • Female
  • Flow Cytometry
  • Immunosuppression Therapy
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Phosphorylation
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes / immunology

Substances

  • Cytokines
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Arginase
  • Dinoprostone