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IgE-Antibody-Dependent Immunotherapy of Solid Tumors: Cytotoxic and Phagocytic Mechanisms of Eradication of Ovarian Cancer Cells^1,2

Sophia N. Karagiannis^3,*, Marguerite G. Bracher^*, James Hunt^*, Natalie McCloskey^*, Rebecca L. Beavil^*, Andrew J. Beavil^*, David J. Fear^*, Richard G. Thompson, Nicholas East, Frances Burke, Robert J. Moore, David D. Dombrowicz, Frances R. Balkwill and Hannah J. Gould^*

^* Randall Division of Cell and Molecular Biophysics, New Hunt’s House, King’s College London, Guy’s Campus, London, United Kingdom; Centre for Translational Oncology, Institute of Cancer and the CR-UK Clinical Centre, Barts and The London, Queen Mary’s School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, United Kingdom; and Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche 17, Institut Pasteur de Lille, Unité 547, Lille, France

Abs have a paramount place in the treatment of certain, mainly lymphoid, malignancies, although tumors of nonhemopoietic origin have proved more refractory ones. We have previously shown that the efficacy of immunotherapy of solid tumors, in particular ovarian carcinoma, may be improved by the use of IgE Abs in place of the conventional IgG. An IgE Ab (MOv18 IgE) against an ovarian-tumor-specific Ag (folate binding protein), in combination with human PBMC, introduced into ovarian cancer xenograft-bearing mice, greatly exceeded the analogous IgG1 in promoting survival. In this study, we analyzed the mechanisms by which MOv18 IgE may exert its antitumor activities. Monocytes were essential IgE receptor-expressing effector cells that mediated the enhanced survival of tumor-bearing mice by MOv18 IgE and human PBMC. Monocytes mediated MOv18 IgE-dependent ovarian tumor cell killing in vitro by two distinct pathways, cytotoxicity and phagocytosis, acting respectively through the IgE receptors FcRI and CD23. We also show that human eosinophils were potent effector cells in MOv18 IgE Ab-dependent ovarian tumor cell cytotoxicity in vitro. These results demonstrate that IgE Abs can engage cell surface IgE receptors and activate effector cells against ovarian tumor cells. Our findings offer a framework for an improved immunotherapeutic strategy for combating solid tumors.

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 study was supported by the Association for International Cancer Research, U.K.

² 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.

³ Address correspondence and reprint requests to Dr. Sophia N. Karagiannis, Randall Division of Cell and Molecular Biophysics, King’s College London, Room 3.8, New Hunt’s House, Guy’s Campus, St Thomas’s Street, London, U.K. E-mail address: sophia.karagiannis{at}kcl.ac.uk

⁴ Abbreviations used in this paper: ADCP, Ab-dependent cell-mediated phagocytosis; ADCC, Ab-dependent cell-mediated cytotoxicity; NIP, 4-hydroxy-3-nitro-phenacetyl; sFcRI, soluble FcRI -chain; PI, propidium iodide; SL, spontaneous loss.

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