Mechanisms of target recognition and destruction in macrophage-mediated tumor cytotoxicity

Macrophages can be activated to kill neoplastic cells selectively and efficiently. Recent studies from his laboratory on mechanisms of target recognition and injury operative in such lysis have centered on the binding of tumor targets to the secretion of a cytolytic protease (cytolytic factor (CF]) by activated murine macrophages. Activated macrophages selectively and extensively bind neoplastic cells; nonselective binding of a low degree is seen between numerous cell pairs. The selective binding of three nonadherent tumors, which is much firmer than the nonselective binding, appears to depend on shared recognition structures contained within plasma membranes of the three tumors. Activated macrophages also secrete a potent, cytolytic, serine protease of molecular weight approximately 40,000. Secretion of CF is closely correlated with activation for cytolysis, and specific protease inhibitors of CF block macrophage-mediated cytotoxicity. Binding of tumor cells to activated macrophages triggers augmented secretion of CF. Several lines of evidence indicate that the capacity for selective binding and the capacity for secreting CF are separate and independently regulated functions of activated macrophages and that each is necessary but not sufficient for completion of macrophage-mediated tumor cytotoxicity. Analysis of the complete lytic interaction between activated macrophages and tumor cells suggests that binding and then secretion of CF are sequentially involved. These data have been integrated into a minimal hypothetical model, which suggests that macrophage-mediated tumor cytotoxicity is a multistep event encompassing 1) selective binding of tumor cells to the surface of activated macrophages and 2) secretion of multiple lytic effector substances, including CF, from the activated macrophages.