Cytolytic interactions between murine macrophages, tumor cells, and monoclonal antibodies: characterization of lytic conditions and requirements for effector activation.

Abstract

Because of recent successes in inducing the effective rejection of neoplasms in vivo by administration of monoclonal antibodies (MAb), we analyzed lytic interactions in vitro that occur between macrophages and several combinations of tumor targets and MAb that can lead to such successful immunotherapy. Murine macrophages, interacting with MAb of the IgG1, IgG2a, IgG2b, and IgG3 isotypes directed against SW-1116 carcinoma cells, destroyed the tumor targets efficiently over 24 to 48 hr in vitro. Lysis was dependent on both concentration of the MAb and density of the macrophages. Binding and lysis of the targets in the presence of MAb of the IgG2a isotype was dependent on intact Fc gamma 2aR on the macrophages; target binding was necessary but not sufficient for subsequent lysis. The lytic step appeared to have an oxidative basis, at least in part, as shown by inhibition of lysis with a nonspecific scavenger of H2O2 or under either anaerobic or glucose-deprived conditions. TG-elicited or pyran-elicited macrophages, which are incompletely activated for antibody independent kill of tumor cells, were effective in mediating ADCC. By contrast, macrophages fully activated for direct cytolysis by administration of BCG or Propionibacterium acnes in vivo or by MAF and LPS in vitro, had diminished capacity for ADCC. A spectrum of five other tumor cells and antibodies, four of which are also involved in successful models of immunotherapy in vivo, were also killed over 48 hr more effectively by thioglycolate-elicited than by BCG-activated macrophages. Taken together, the data indicate that macrophages can lyse tumor cells in an ADCC reaction that has application to some models of the destruction of tumors in vivo, but that the lysis is slow and requires the macrophages to be activated in a specific way(s).