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

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

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1
University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.

Abstract

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.

PMID:
19261929
PMCID:
PMC2698586
DOI:
10.1189/jlb.0708446
[Indexed for MEDLINE]
Free PMC Article
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