GAMMA-INTERFERON INHIBITS FC RECEPTOR II-MEDIATED PHAGOCYTOSIS OF TUMOR-CELLS BY HUMAN MACROPHAGES

In vitro, monocyte-derived macrophages (MDM) are capable of efficient antibody-mediated phagocytosis of human nucleated tumor cells. These M DM express on their cell surface all three classes of Fc receptors for IgG (Fc gamma R). Fc gamma R specificity for murine antibody isotype allowed us to examine the phagocytic role of Fc gamma RII on control a nd gamma-interferon (IFN-gamma)-primed MDM. Monoclonal antibody 520C9 (IgG1) mediates phagocytosis through Fc gamma RII. This monoclonal ant ibody is directed against the HER-2/neu protooncogene product overexpr essed on a variety of adenocarcinomas including the breast carcinoma c ell line SK-BR-3. Our results showed that IFN-gamma treatment of diffe rentiated MDM (days 8-12 in culture) inhibited Fc gamma RII-mediated p hagocytosis in a dose-dependent manner with negative effects noted at doses as low as 0.1 units/ml. The percentage reduction in antibody-med iated phagocytosis observed following IFN-gamma priming (40 units/ml f or 18 h) ranged from 23-89% of control. The inhibitory effect was evid ent when exposure to IFN-gamma was transient. Fc gamma RII expression was not altered by IFN-gamma treatment. In our model, IFN-gamma did no t up-regulate or down-regulate HER-2/neu protein expression on our tar gets or affect the level of CD14 antigen expression on our MDM. Althou gh IFN-gamma is a potent activator of monocytes/macrophages and can en hance certain tumoricidal mechanisms, our data show that antibody-depe ndent phagocytosis through the type II Fc receptor is inhibited by IFN -gamma priming. Nonspecific phagocytosis was not affected.