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Circulating Myeloid Dendritic Cells of Advanced Cancer Patients Result in Reduced Activation and a Biased Cytokine Profile in Invariant NKT Cells¹

Hans J. J. van der Vliet^2,*,, Ruojie Wang^*, Simon C. Yue^*, Henry B. Koon^*, Steven P. Balk^* and Mark A. Exley^*

^* Cancer Biology Program, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; and Department of Medical Oncology, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands

CD1d-restricted invariant NKT (iNKT) cells play important regulatory roles in various immune responses, including antitumor immune responses. Previous studies have demonstrated quantitative and qualitative defects in iNKT cells of cancer patients, and these defects are clinically relevant as they are associated with poor prognosis. In this study we demonstrate that defects in the iNKT cell population can, at least in part, be attributed to defective interactions between iNKT cells and CD1d-expressing circulating myeloid dendritic cells (mDC), as mDC of patients with advanced melanoma and renal cell cancer reduced the activation and Th1 cytokine production of healthy donor-derived iNKT cells. Interestingly, this reduced activation of iNKT cells was restricted to patients with low circulating iNKT cell numbers and could be reversed by IL-12 and in part by the neutralization of TGF-β, but it was further reduced by the neutralization of IL-10 in vitro. Additional experiments revealed discordant roles for TGF-β and IL-10 on human iNKT cells, because TGF-β suppressed iNKT cell activation and proliferation and IFN- production while IL-10 was identified as a cytokine involved in stimulating the activation and expansion of iNKT cells that could subsequently suppress NK cell and T cell responses.

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 the Netherlands Organization for Scientific Research NWO-TALENT Grant and Grant 920-03-142, a Dutch Cancer Society (KWF) Academic Grant, National Institutes of Health Grants R01 DK066917 and R01 AI42955, and the Dana Farber/Harvard Cancer Center Melanoma Specialized Program of Research Excellence Grant P50 CA93683.

² Address correspondence and reprint requests to Dr. Hans J. J. van der Vliet, Vrije Universiteit Medisch Centrum, Department of Medical Oncology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. E-mail address: jj.vandervliet{at}vumc.nl

³ Abbreviations used in this paper: iNKT, CD1d-restricted invariant NKT (cell); -GalCer, -galactosylceramide; DC, dendritic cell; mDC, myeloid DC; moDC, monocyte-derived DC; pDC, plasmacytoid DC; RCC, renal cell cancer; rh, recombinant human.