The mechanism of augmentation of natural killer cell activity by syngeneic tumor cells: role of macrophage-derived factor in NK boosting.

Abstract

The role of natural killer (NK) cells in controlling tumor growth was investigated using an NK-susceptible (c127v-IC2) and an NK-insusceptible (c127av) subline of the lymphoma L5178Y. Syngeneic DBA/2 mice inoculated intraperitoneally with c127v-IC2 tumor cells survived significantly longer than did c127av-bearing mice. Similarly, c127v-IC2, but not c127av tumor cells, were found to augment NK activity of spleen and peritoneal exudate cells in both DBA/2 and BALB/c nu/nu mice when inoculated into the peritoneal cavity. C127v-IC2 tumor cells incubated with either DBA/2 or BALB/c nu/nu spleen cells in vitro boosted NK activity and induced the production of gamma-type interferon (IFN), whereas incubation with c127av tumor cells induced neither NK activity nor IFN. Two kinds of cells cooperated in the production of IFN in response to c127v-IC2 tumor cells, namely, cells which were nonadherent, bore asialo-GM1, NK-1.2 and a low level of Thy-1.2 antigen and thus closely resembled NK cells, and those which were adherent and phagocytic and lacked both asialo-GM1 and NK-1.2 markers, presumably macrophages. Further analysis strongly suggested that c127-v-IC2 tumor cells stimulate macrophages to produce factor(s) which can induce the production of IFN by NK cells. The induced IFN was shown to be of the gamma type by its lability at pH 2.0 and insusceptibility to anti-IFN alpha, beta serum. This suggests a novel pathway for NK cell activation, and strongly supports the importance of macrophages and NK cells in natural resistance against certain tumors.