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Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice¹

H. Lee Moffitt Cancer Center and Research Institute and Department of Molecular Medicine, University of South Florida, Tampa, FL 33612

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of cells that play a critical role in tumor associated immune suppression. In an attempt to identify a specific subset of MDSC primarily responsible for immunosuppressive features of these cells, 10 different tumor models were investigated. All models showed variable but significant increase in the population of MDSC. Variability of MDSC expansion in vivo matched closely the effect of tumor cell condition medium in vitro. MDSC consists of two major subsets of Ly6G⁺Ly6C^low granulocytic and Ly6G^–Ly6C^high monocytic cells. Granulocytic MDSC have increased level of reactive oxygen species and undetectable level of NO whereas monocytic MDSC had increased level of NO but undetectable levels of reactive oxygen species. However, their suppressive activity per cell basis was comparable. Almost all tumor models demonstrated a preferential expansion of granulocytic subset of MDSC. We performed a phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells: CD115, CD124, CD80, PD-L1, and PD-L2. Although substantial proportion of MDSC expressed those molecules no differences in the level of their expression or the proportion, positive cells were found between MDSC and cells from tumor-free mice that lack immune suppressive activity. The level of MDSC-mediated T cell suppression did not depend on the expression of these molecules. These data indicate that suppressive features of MDSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.

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 Grant CA84488 from the National Institutes of Health (to D.I.G.). This work was supported in part by the Analytic Microscopy and Flow Cytometry Core Facility at the H. Lee Moffitt Cancer Center.

² J.-I.Y. and S.N. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Dmitry I. Gabrilovich, H. Lee Moffitt Cancer Center and Research Institute, 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; TCCM, tumor cell conditioned medium; IMC, immature myeloid cell.