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Mechanism Regulating Reactive Oxygen Species in Tumor-Induced Myeloid-Derived Suppressor Cells¹

Cesar A. Corzo^*, Matthew J. Cotter^*, Pingyan Cheng^*, Fendong Cheng^*, Sergei Kusmartsev^2,*, Eduardo Sotomayor^*,, Tapan Padhya^*,, Thomas V. McCaffrey^*,, Judith C. McCaffrey^*, and Dmitry I. Gabrilovich^3,*,

^* H. Lee Moffitt Cancer Center and Research Institute and Departments of Otolaryngology and Oncologic Sciences University of South Florida, Tampa, FL, 33612

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47^phox and gp91^phox, compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

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 This work was supported by National Institutes of Health Grant 1RO1 CA 84488 (to D.I.G.) and F31 CA 123708-02 fellowship (to C.A.C.). This work has been supported in part by the Analytic Microscopy and Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center.

² Current address: Department of Urology, University of Florida, Gainesville, FL 32601.

³ Address correspondence and reprint requests to Dmitry Gabrilovich, H. Lee Moffitt Cancer Center, MRC 2067, 12902 Magnolia Drive, Tampa, FL 33612. E-mail address: dmitry.gabrilovich{at}moffitt.org

⁴ Abbreviations used in this paper: MDSC, Myeloid-derived suppressor cell; ROS, reactive oxygen species; qRT-PCR, quantative real-time PCR; ChIP, chromatin immunoprecipitation; ES cell, embryonic stem cell; IMC, immature myeloid cell; NOX2, NADPH oxidase; WT, wild type; TCCM, tumor-cell-conditioned medium; KO, knock out; LIF, leukemia inhibitory factor; CGD, chronic granulomatous disease; DCFDA, dichlorodihydrofluorescein diacetate.

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The JI 2009 182: 5157-5158. [Full Text]