Effect of recombinant human tumor necrosis factor alpha on the induction of antibody-dependent cellular cytotoxicity in the treatment of established B16 melanoma liver nodules.

Abstract

Incubation of C3H/Hen thymocytes in the presence of recombinant human tumor necrosis factor alpha (TNF) and interleukin-2 (IL-2) augmented the generation of antibody-dependent cellular cytotoxicity (ADCC) when compared to cells cultured in TNF or IL-2 alone. This effect was optimal when 100-200 units/ml IL-2 was used together with 10(3)-10(4) units/ml TNF. TNF alone at any concentration could not mediate the induction of ADCC. Similar to the results obtained in vitro, TNF, when given alone, had no effect on the generation of ADCC in vivo. The addition, however, of TNF to IL-2, given at 10,000 and 20,000 but not 40,000 units, enhanced the IL-2-induced ADCC on a per-cell basis. Furthermore, TNF enhanced the total ADCC activity in various organs including the liver, spleen and thymus as a result of an increase in the number of mononuclear cells isolated from these organs. The increase in total ADCC activity was optimal when 110,000-220,000 units (5-10 micrograms) TNF were employed together with IL-2. The combined treatment with TNF and IL-2 also increased the intracellular benzyloxycarbonyl-1-L-lysine-thiobenzyl-ester esterase content in cells isolated from the livers of mice treated with these cytokines. On the basis of these results we treated mice bearing a single B16 melanoma nodule with TNF and TNF + IL-2 given with or without anti-B16 monoclonal antibody. We found that TNF administration augmented the anti-tumor effect of specific anti-B16 antibodies, and the addition of IL-2 further increased this anti-tumor effect.