EARLY-APPEARING TUMOR-INFILTRATING NATURAL-KILLER-CELLS PLAY AN IMPORTANT ROLE IN THE NITRIC-OXIDE PRODUCTION OF TUMOR-ASSOCIATED MACROPHAGES THROUGH THEIR INTERFERON-PRODUCTION

Both natural killer (NK) cells and macrophages are thought to be the m ain effecters responsible for early antitumor defense. In this study, we investigated the role of tumor-infiltrating NK cells in initiating nitric oxide (NO) production by tumor-associated macrophages (TAM). Th e in vivo depletion of NK cells prior to the i.p. inoculation of melan oma cells resulted in a significant decrease in the NO production of t he TAM prepared from the peritoneal exudate cells (PEG). Such prior NK cell depletion also decreased the ability of TAM to show any antitumo r activity in vitro. The addition of N-G-monomethyl-L-arginine (Me-L-A rg) to the culture partially inhibited the ability of TAM to suppress the proliferation of melanoma cells and also decreased their cytolytic activity against melanoma cells. These results suggest that the TAM e xhibited both cytostatic and cytolytic activities through their NO pro duction. In an in vivo assay, the administration of Me-L-Arg permitted the more rapid growth of i.p. inoculated melanoma cells compared with the control. On the other hand, the decreased NO production of TAM, r esulting from the prior NK cell depletion, was restored by the i.p. ad ministration of interferon gamma (IFN gamma). In addition, the in vivo administration of anti-IFN gamma mAb into mice inoculated i.p. with m elanoma cells also significantly decreased the NO production of TAM in peritoneal exudate cells. Furthermore, the tumorinfiltrating NK cells produced a considerable level of IFN gamma. Overall, these results in dicate that early-appearing tumorinfiltrating NK cells play an importa nt role in the NO production of TAM through their IFN gamma production .