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Differential Effect of Cytokine Treatment on Fc Receptor I- and Fc Receptor I-Mediated Tumor Cytotoxicity by Monocyte-Derived Macrophages

Tibor Keler^1,*, Paul K. Wallace, Laura A. Vitale^*, Christina Russoniello^*, Karuna Sundarapandiyan^*, Robert F. Graziano^* and Yashwant M. Deo^*

^* Medarex, Inc., Annandale, NJ 08801; and Department of Microbiology, Dartmouth Medical School, Lebanon, NH 03756

Macrophages represent an important effector cell for Ab-mediated tumor therapy. Previous studies have documented that cytokines can influence Fc receptor (FcR) expression and function. In this study we examined the tumoricidal activities of the type I receptors for IgG (FcRI) and the IgA FcR (FcRI) on monocyte-derived macrophages (MDM) cultured in the presence of IFN-, M-CSF, or GM-CSF. Bispecific Abs were used to target a Her2/neu breast carcinoma cell line, SKBR-3, to FcRI or FcRI on MDM. Although FcRI and FcRI share a common signaling pathway contingent on association with the -chain (FcR subunit), a marked difference in their efficiency in mediating tumoricidal functions was seen in response to specific cytokines. M-CSF- and GM-CSF-treated MDM mediated efficient phagocytosis of SKBR-3 cells by FcRI and FcRI; however, IFN--treated MDM phagocytosed tumor cells only with the FcRI-directed bispecific Abs. Similarly, IFN--cultured MDM lysed tumor cells more efficiently via FcRI then by FcRI as measured in Ab-dependent cellular cytotoxicity assays. Conversely, GM-CSF-treated MDM mediated more efficient lysis of tumor cells via FcRI than FcRI, while M-CSF-cultured MDM were relatively less efficient in mediating Ab-dependent cellular cytotoxicity through either receptor. With the exception of IFN--mediated enhancement of FcRI expression and FcRI -chain complexes, the regulation of FcRI- or FcRI-mediated activity occurred without significant change in either receptor expression or total complexes with subunit. These data suggest that the efficiency of Ab-mediated tumor therapy, which depends on FcR effector cell functions, may be modified by the use of specific cytokines.

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