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Originally published online as doi:10.1189/jlb.0708446 on March 4, 2009

Published online before print March 4, 2009
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(Journal of Leukocyte Biology. 2009;85:996-1004.)
© 2009 by Society for Leukocyte Biology

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

Stephanie K. Bunt1, Virginia K. Clements1, Erica M. Hanson, Pratima Sinha and Suzanne Ostrand-Rosenberg2

Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland, USA

2 Correspondence: Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. E-mail: srosenbe{at}umbc.edu

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-1β-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.

Key Words: tumor-induced immune suppression • inflammation • T cell activation