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* Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250; and
University of Pennsylvania Medical Center, Pulmonary, Allergy, and Critical Care Division, Philadelphia, PA 19104
Although the immune system has the potential to protect against malignancies, many individuals with cancer are immunosuppressed. Myeloid-derived suppressor cells (MDSC) are elevated in many patients and animals with tumors, and contribute to immune suppression by blocking CD4+ and CD8+ T cell activation. Using the spontaneously metastatic 4T1 mouse mammary carcinoma, we now demonstrate that cross-talk between MDSC and macrophages further subverts tumor immunity by increasing MDSC production of IL-10, and by decreasing macrophage production of IL-12. Cross-talk between MDSC and macrophages requires cell-cell contact, and the IL-12 decrease is dependent on MDSC production of IL-10. Treatment with the chemotherapeutic drug gemcitabine, which reduces MDSC, promotes rejection of established metastatic disease in IL-4R
–/– mice that produce M1 macrophages by allowing T cell activation, by maintaining macrophage production of IL-12, and by preventing increased production of IL-10. Therefore, MDSC impair tumor immunity by suppressing T cell activation and by interacting with macrophages to increase IL-10 and decrease IL-12 production, thereby promoting a tumor-promoting type 2 response, a process that can be partially reversed by gemcitabine.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 These studies were supported by the National Institutes of Health (R01CA52527, R01CA84232, RO1CA118550, and PO1 CA66726) and the Susan G. Komen Foundation (BCTR0503885).
2 Address correspondence and reprint requests to Dr. Suzanne Ostrand-Rosenberg, Department of Biological Sciences, University of Maryland, 1000 Hilltop Circle, Baltimore, MD 21250. E-mail address: srosenbe{at}umbc.edu
3 Abbreviations used in this paper: MDSC, myeloid-derived suppressor cell; DC, dendritic cell; HA, influenza hemagglutinin; nor-NOHA, Nw-hydroxyl-nor-L-arginine; PDCA, plasmacytoid DC; PEC, peritoneal exudate cell.
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