PGE(2)-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells

Immunol Invest. 2012;41(6-7):635-57. doi: 10.3109/08820139.2012.695417.


Myeloid-derived suppressor cells (MDSCs) are critical mediators of tumor-associated immune suppression, with their numbers and activity strongly increased in most human cancers and animal models. MDSCs suppress anti-tumor immunity through multiple mechanisms, including the manipulation of arginine and tryptophan metabolism by such factors as arginase (Arg), inducible nitric oxide synthase (iNOS/NOS2), and indoleamine-2,3-dioxygenase (IDO). Prostaglandin E(2) (PGE(2)), a mediator of chronic inflammation and tumor progression, has emerged as a key molecule in MDSC biology. PGE(2) promotes MDSC development and their induction by additional factors, directly suppresses T cell immune responses and participates in the induction of other MDSC-associated suppressive factors, including Arg, iNOS and IDO. It further promotes MDSC recruitment to tumor environments through the local induction of CXCL12/SDF-1 and the induction and stabilization of the CXCL12 receptor, CXCR4, on tumor-associated MDSCs. The establishment of a positive feedback loop between PGE(2) and cyclooxygenase 2 (COX-2), the key regulator of PGE(2) synthesis, stabilizes the MDSC phenotype and is required for their suppressive function. The central role of PGE(2) in MDSC biology provides for a feasible target for counteracting MDSC-mediated immune suppression in cancer.

Publication types

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

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / immunology*
  • Arginine / metabolism*
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / immunology
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / immunology*
  • Dinoprostone / metabolism*
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Mice
  • Myeloid Progenitor Cells / immunology
  • Myeloid Progenitor Cells / metabolism*
  • Myeloid Progenitor Cells / pathology
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / immunology
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / immunology
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology


  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Receptors, CXCR4
  • Arginine
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • ARG1 protein, human
  • Arginase
  • Dinoprostone