Reversal of suppression of lymphokine-activated killer cells by transforming growth factor-beta in ovarian carcinoma ascitic fluid requires interleukin-2 combined with anti-CD3 antibody

Abstract

Ascitic fluid from human ovarian carcinoma (AF) has been shown to inhibit IL-2-induced lymphokine-activated killer (LAK) cell generation from peripheral blood mononuclear cells (PBMC) resulting from the presence of biologically active transforming growth factor-beta (TGF-beta). A 50% concentration of AF completely suppressed the LAK response to 100 units IL-2/ml and only partial reversal (less than 50%) could be achieved by increasing the IL-2 concentration to 1000 units/ml. We evaluated the ability of tumor necrosis factor-alpha (TNF-alpha, 1-1000 ng/ml) and anti-CD3 antibody (alpha-CD3, 1-100 ng/ml) to reverse AF-mediated suppression of IL-2-stimulated LAK generation. TNF-alpha alone did not generate significant LAK activity, but in the presence of suboptimal concentrations of IL-2 (10 and 100 units/ml), TNF-alpha significantly boosted the generation of LAK, but was unable to significantly reverse AF-mediated suppression of the IL-2 response (even at 1000 units/ml). In contrast, alpha-CD3 alone generated LAK activity at concentrations as low as 1 ng/ml and markedly enhanced generation of LAK activity when added to suboptimal concentrations of IL-2. alpha-CD3 combined with IL-2 significantly reversed AF suppression at 100 units IL-2/ml and at 1000 units/ml completely reversed suppression by two of three highly suppressive samples of AF. Significant reversal occurred with the third AF sample. It may be possible to overcome TGF-beta-mediated suppression by measures other than by increasing the IL-2 concentration.