Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4

J Leukoc Biol. 2009 Jun;85(6):996-1004. doi: 10.1189/jlb.0708446. Epub 2009 Mar 4.


Myeloid-derived suppressor cells (MDSC) are potent inhibitors of anti-tumor immunity that facilitate tumor progression by blocking the activation of CD4(+) and CD8(+) T cells and by promoting a type 2 immune response through their production of IL-10 and down-regulation of macrophage production of IL-12. MDSC accumulate in many cancer patients and are a significant impediment to active cancer immunotherapies. Chronic inflammation has been shown recently to enhance the accumulation of MDSC and to increase their suppression of T cells. These findings led us to hypothesize that inflammation contributes to tumor progression through the induction of MDSC, which create a favorable environment for tumor growth. As chronic inflammation also drives type 2 immune responses, which favor tumor growth, we asked if inflammation mediates this effect through MDSC. We find that IL-1beta-induced inflammation increased IL-10 production by MDSC and induces MDSC, which are more effective at down-regulating macrophage production of IL-12 as compared with MDSC isolated from less-inflammatory tumor microenvironments, thereby skewing tumor immunity toward a type 2 response. Inflammation heightens MDSC phenotype by signaling through the TLR4 pathway and involves up-regulation of CD14. Although this pathway is well-recognized in other myeloid cells, it has not been implicated previously in MDSC function. These studies demonstrate that MDSC are an intermediary through which inflammation promotes type 2 immune responses, and they identify the TLR4 pathway in MDSC as a potential target for down-regulating immune suppression and promoting anti-tumor immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Inflammation / immunology*
  • Interleukin-10 / biosynthesis
  • Interleukin-12 / biosynthesis
  • Interleukin-1beta
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation / drug effects
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology*
  • Receptor Cross-Talk*
  • Signal Transduction* / drug effects
  • Toll-Like Receptor 4 / metabolism*
  • Up-Regulation / drug effects


  • Interleukin-1beta
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Interleukin-10
  • Interleukin-12