Rapid decay of tumoricidal activity and loss of responsiveness to lymphokines in inflammatory macrophages

The ability of inflammatory tissue macrophages harvested on glass coverslips implanted in the s.c. tissue of C57BL/6 mice to kill tumor cells in vitro has been examined. Macrophage present on coverslips implanted for less than 4 days are devoid of spontaneous tumoricidal activity but can be rendered cytotoxic for syngeneic and allogeneic tumor cells in vitro by incubation in vitro with lymphokines release by mitogen-stimulated lymphocytes. Inflammatory macrophages on coverslips implanted for 4 to 7 days show significant spontaneous cytotoxicity for tumor cells in vitro, and their tumoricidal activity is further increased by additional incubation in vitro with lymphokines. With progression, the inflammatory macrophages harvested on coverslips implanted for longer than 7 days lack spontaneous cytotoxic activity and are also resistant to activation by lymphokines in vitro. These alterations in tumoricidal activity and responsiveness to lymphokines are accompanied by a marked reduction in the number of peroxidase-positive macrophages within the population, suggesting that maintenance of tumoricidal activity requires continuous influx of new peroxidase-positive macrophages from the circulation. Previously activated macrophages which have lost their tumoricidal activity and become refractory to reactivation by lymphokines in the extracellular environment can be reactivated by treatment in vitro with liposomes containing encapsulated lymphokines.