PROTECTIVE EFFECTS OF INTERFERON-GAMMA ON SQUAMOUS-CELL CARCINOMA OF HEAD AND NECK TARGETS IN ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY MEDIATED BY HUMAN NATURAL-KILLER-CELLS

An in vitro model of antibody-dependent cellular cytotoxicity (ADCC) w as established, using squamous-cell carcinoma of the head and neck (SC CHN) targets, human/mouse chimeric monoclonal antibodies (cMAbs) SF-25 and 323/A3 and human peripheral blood mononuclear cells (PBMC). We pr eviously showed that natural killer (NK) cells are the main effector p opulation mediating ADCC in the presence of the cMAbs. ADCC was signif icantly inhibited by the overnight pre-treatment of SCCHN targets with exogenous interferon-gamma (IFN-gamma). This inhibition was dose-depe ndent, reproducible and consistently observed with various SCCHN cell lines. SCCHN cells pre-treated with IFN-gamma had a significantly high er expression of intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class I antigens compared with untrea ted target cells. No differences in expression of the SCCHN-associated antigens on these targets or in the formation of NK-SCCHN conjugates were found, using flow cytometry. IFN-gamma-pre-treated SCCHN cells we re less effective in competing with untreated targets in cold target i nhibition assays and in inducing cytokine production from NK cells in co-incubation experiments. Protective effects of IFN-gamma on target c ell sensitivity to lysis were blocked by pre-treatment of target cells with actinomycin-D or cycloheximide. The susceptibility of the target cells was restored by removal of MHC class I antigens from their surf ace by acid stripping before ADCC. Our results suggest that the decrea sed ADCC seen with SCCHN targets pre-treated with IFN-gamma is related to post-binding events, possibly altered signaling from targets to ef fector cells, and requires protein synthesis in the target cells. (C) 1996 Wiley-Liss, Inc.