Colony-stimulating factor enhancement of myeloid effector cell cytotoxicity towards neuroectodermal tumour cells.

Abstract

We conducted experiments to determine the optimal conditions for colony-stimulating factor-enhanced neutrophil- and mononuclear phagocyte-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) using monoclonal antibodies to disialogangliosides expressed on neuroectodermal tumour target cells. Neutrophil ADCC was most effective at effector:target ratios of 100:1, with maximal cytotoxic responses to melanoma target cells generated by 3 h. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) were the most potent stimulators of neutrophil ADCC, and enhanced ADCC activity was inhibited in the presence of antibody to Fc receptor type II (FcRII). GM-CSF and macrophage colony-stimulating factor (M-CSF) treatment of freshly isolated monocytes inhibited antibody-independent cytotoxicity but enhanced antibody-dependent responses. After 3 d in culture with CSF, 3-10-fold enhancement of ADCC against melanoma target cells was observed at effector:target cell ratios of 10:1. Greatest stimulation of macrophage ADCC was obtained when GM-CSF, M-CSF or interleukin 3 (IL-3) were used in conjunction with a secondary stimulus. Although gamma interferon (gamma-IFN) did not augment the cytotoxic capability of GM-CSF- and IL-3-stimulated macrophages, prominent cytotoxic enhancement was seen when M-CSF-stimulated macrophages were exposed to gamma-IFN. A chimaeric mouse/human monoclonal antibody was found to be equivalent in activity to the murine antibody in neutrophil ADCC; however, in macrophage ADCC assays with submaximal effector cell stimulation, the chimaeric antibody was associated with a two-fold greater response. These studies indicate that under specific conditions, CSFs capable of increasing the number and functional activity of mature myeloid effector cells enhance antibody-dependent cytotoxicity to neuroectodermal tumour target cells.