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Macrophage Migration Inhibitory Factor Contributes to the Immune Escape of Ovarian Cancer by Down-Regulating NKG2D¹

Mathias Krockenberger^*,, Yvonne Dombrowski^*,, Claudia Weidler^*,, Monika Ossadnik^*,, Arnd Hönig^*,, Sebastian Häusler^*, Heike Voigt, Jürgen C. Becker, Lin Leng^¶, Alexander Steinle, Michael Weller^#, Richard Bucala^¶,||, Johannes Dietl^* and Jörg Wischhusen^2,*,

^* Department for Obstetrics and Gynecology, Interdisciplinary Center for Clinical Research, and Clinical research group KFO 124, University of Würzburg, Würzburg, Germany; Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany; ^¶ Department of Medicine and ^|| Department of Pathology, Yale University School of Medicine, New Haven, CT 06520; and ^# Department of Neurology, University Hospital Zurich, Zurich, Switzerland

The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.

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 grants from the Interdisciplinary Center for Clinical Research Würzburg (to J.W.) and the National Institutes of Health (to L.L. and R.B.).

² Address correspondence and reprint requests to Dr. Jörg Wischhusen, Interdisciplinary Center for Clinical Research Junior Research Group "Tumor Progression and Immune Escape," Department of Gynecology, University of Würzburg, Josef-Schneider-Strasse 4, D-97080 Würzburg, Germany. E-mail address: Wischhusen_J{at}klinik.uni-wuerzburg.de

³ Abbreviations used in this paper: OvCA, ovarian carcinoma; MIF, macrophage migration inhibitory factor; NKG2D, natural killer group 2D; SFI, specific fluorescence intensity; SN, supernatant; rh, recombinant human.