The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online September 22, 2008
doi:10.1084/jem.20080132
The Journal of Experimental Medicine, Vol. 205, No. 10, 2235-2249
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Cheng et al.
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ARTICLE

 Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein

Pingyan Cheng1, Cesar A. Corzo1, Noreen Luetteke1, Bin Yu1, Srinivas Nagaraj1, Marylin M. Bui1, Myrna Ortiz1, Wolfgang Nacken3, Clemens Sorg2, Thomas Vogl2, Johannes Roth2, and Dmitry I. Gabrilovich1

1 H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612
2 Institute of Immunology, University of Münster, D-48149 Münster, Germany
3 Institute for Molecular Virology, Center for Molecular Biology of Inflammation, D-48149 Münster, Germany

CORRESPONDENCE Dmitry Gabrilovich: dmitry.gabrilovich{at}moffitt.org

Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer. Mice lacking this protein mounted potent antitumor immune responses and rejected implanted tumors. This effect was reversed by administration of wild-type MDSCs from tumor-bearing mice to S100A9-null mice. Overexpression of S100A9 in cultured embryonic stem cells or transgenic mice inhibited the differentiation of DCs and macrophages and induced accumulation of MDSCs. This study demonstrates that tumor-induced up-regulation of S100A9 protein is critically important for accumulation of MDSCs and reveals a novel molecular mechanism of immunological abnormalities in cancer.

Abbreviations used: ChIP, chromatin immunoprecipitation assay; EB, embryoid body; ES, embryonic stem; FCM, fibroblast-conditioned medium; HPC, hematopoietic progenitor cell; IMC, immature myeloid cell; LIF, leukemia inhibitory factor; MDSC, myeloid-derived suppressor cell; ROS, reactive oxygen species; SCF, stem cell factor; TCM, tumor cell–conditioned medium; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor.

© 2008 Cheng et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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