Distinct signals for antibody-dependent and nonspecific killing of tumor targets mediated by macrophages.

Conditions influencing the generation of antibody-dependent cellular cytotoxicity (ADCC) and several types of nonspecific tumor cell killing by macrophages were compared. Resident mouse peritoneal macrophages and several macrophage cell lines spontaneously display very low levels of ADCC to lymphoma targets. However, ADCC could be greatly stimulated in these macrophage populations by several days of culture with lipopolysaccharide (LPS), tumor promoter phorbol myristic acetate (PMA), and lymphokine (LK) preparations. Fibroblast L cell-conditioned medium (L-CM), a source of activities required for in vitro macrophage colony formation, also augmented ADCC. Two days of preincubation was optimal for stimulation of this cytotoxic activity. In contrast to these results, pretreatment of macrophages with any of the agents inhibitor tumor toxicity induced by nonspecific activating drugs present during the assay. This inverse relation between ADCC and nonspecific killing after pretreatment was obtained with peritoneal cells and two cloned macrophage cell lines. Thus, although the same cell or cell type can mediate both types of killing, the two mechanisms seem to be mediated by distinct states of a macrophage. The ADCC-stimulating agents, LPS, LK, and L-CM, probably have a common pathway of activation, because dexamethasone at 10−6 M inhibited their effect. The factors in the LK and L-CM that stimulate ADCC are distinct from LPS, because the endogenous activities were inactivated by boiling. The activities are also separate from interleukin 2 and myeloid colony-stimulating activities (CSA). A macrophage-type colony-stimulating factor purified from L-CM, CSF-1, had no effect on macrophage tumoricidal activity. ADCC-stimulating activity was not the same as macrophage-activating factor for nonspecific killing of fibrosarcoma targets, because the latter is not found in L-CM. It is concluded that macrophage ADCC and nonspecific cytotoxicity may be regulated by different endogenous signals and may represent different states of stimulated macrophages.