Role of IgE receptors in IgE antibody-dependent cytotoxicity and phagocytosis of ovarian tumor cells by human monocytic cells
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Antibodies directed against tumor-associated antigens are emerging as effective treatments for a number of cancers, although the mechanism(s) of action for some are unclear and still under investigation. We have previously examined a chimeric IgE antibody (MOv18 IgE), against the ovarian tumor-specific antigen, folate binding protein (FBP), and showed that it can direct human PBMC to kill ovarian cancer cells. We have developed a three-color flow cytometric assay to investigate the mechanism by which IgE receptors on U937 monocytes target and kill ovarian tumor cells. U937 monocytes express three IgE receptors, the high-affinity receptor, FcεRI, the low-affinity receptor, CD23, and galectin-3, and mediate tumor cell killing in vitro by two mechanisms, cytotoxicity, and phagocytosis. Our results suggest that CD23 mediates phagocytosis, which is enhanced by upregulation of CD23 on U937 cells with IL-4, whereas FcεRI mediates cytotoxicity. We show that effector : tumor cell bridging is associated with both activities. Galectin-3 does not appear to be involved in tumor cell killing. U937 cells and IgE exerted ovarian tumor cell killing in vivo in our xenograft model in nude mice. Harnessing IgE receptors to target tumor cells suggests the potential of tumor-specific IgE antibodies to activate effector cells in immunotherapy of ovarian cancer.
KeywordsMonocytes Cytotoxicity Phagocytosis Fc Receptors Tumor immunity
Antibody-dependent cell-mediated cytotoxicity
Antibody-dependent cell-mediated phagocytosis
Folate binding protein
Soluble FcεRI α-chain
Carboxy-fluorescein diacetate, succinimidyl ester
We are grateful to Dr. David Fear and Dr. Philippe Gevaert for providing generous technical expertise and advice and to Dr. Pooja Takhar for her helpful critical comments. We thank Ms. Kate Kirwan for expert assistance with the figures. We are grateful to Dr. Marie-Hélène Jouvin, Dr. Jean-Pierre Kinet, Dr. Silvana Canevari, Prof. Fu-Tong Liu, Dr. J. Hopp, and Prof. R. Korngold, for the generous provision of advice and materials. This study was supported by the Association for International Cancer Research, United Kingdom.
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