Human monocyte-derived macrophages (MDM) mediate efficient antibody-dependent cellular cytotoxicity (ADCC) against a variety of human tumor cell types in the presence of an anti-tumor monoclonal antibody. We have recently shown that the mechanism of this ADCC in our in vitro system involves phagocytosis of intact tumor cells. Some forms of macrophage ADCC have been reported to be inhibited by serum immunoglobulin, which competes with monoclonal antibodies for binding to the high-affinity Fc receptor (FcRI). In this study we investigated the role of the three macrophage FcR-γ in antibody-dependent tumor cell phagocytosis. Hybridoma cells bearing surface antibody directed against either of the two low-affinity Fc receptors (FcRII or FcRIII) were efficiently phagocytosed by MDM, compared to hybridomas bearing irrelevant antibody. Soluble anti-receptor antibodies against FcRII and FcRIII were able to inhibit ADCC but only when both antibodies were simultaneously present. These data suggest that either low-affinity Fc receptor is capable of functioning independently to mediate phagocytosis of tumor cells. Consistent with a mechanism involving the low-affinity receptors rather than FcRI, antibody-dependent phagocytosis occurred in the presence of human serum, purified human IgG, and irrelevant murine antibody. Greater than 75% of the MDM in our culture system were able to ingest tumor cells when a suitable target was available. Optimal phagocytosis occurred at monoclonal antibody concentrations of 10–100 ng/ml. Like other forms of macrophage phagocytosis, ingestion of tumor cells required the presence of divalent cations (either Ca2+ or Mg2+) and an intact actin cytoskeleton (as indicated by sensitivity to cytochalasin D). Because FcRI is normally occupied in vivo by serum immunoglobulin, the participation of low-affinity FcR in tumor cell phagocytosis is potentially important in establishing the in vivo applicability of this efficient form of cytotoxicity.
Supported in part by National Institutes of Health Grant CA-33049; American Cancer Society Grant IM521; the Friends of Children Foundation, Toys-R-Us Foundation, Inc.; and the Robert Steel Foundation.