Down-regulation of human natural killer activity against tumors by the neutrophil myeloperoxidase system and hydrogen peroxide

There is growing evidence that natural killer (NK) cells play an important role in immune surveillance against tumors and certain infections. The coexistence of activated neutrophils with lymphocytes in tumor masses and inflammatory tissues suggests the possibility of interaction between secreted neutrophil products and nearby lymphocytes. We examined the susceptibility of lymphocyte NK activity to oxidative injury by the neutrophil myeloperoxidase (MPO) system and H₂O₂ with the use of a cellfree model system. Exposure of human mononuclear leukocytes (MNL) to MPO, an H₂O₂-generating system (glucose + glucose oxidase), and a halide (Cl^- or I^-) resulted in marked suppression of MNL-NK activity, as measured by ⁵¹Cr release from K562 tumor targets (p < 0.001). This suppression was dependent on the presence and activity of each system component and was blocked by azide and catalase, but not by heated catalase. In spite of the marked functional suppression of NK activity, MNL viability was more than 95% and target binding frequency was not affected. NK suppression was reversible after 24 h in culture. The mechanism of suppression was dependent on the amount and rate of H₂O₂ delivered, and on MNL number. MPO was essential when H₂O₂ flux was low or when MNL numbers were high. As H₂O₂ flux increased or MNL numbers decreased, NK suppression gradually became MPO-independent and was mediated by H₂O₂ alone. The ability of the MPO system to compromise lymphocyte NK function may explain the in vitro inhibition of NK activity of mixed cell populations by the tumor promoter phorbol esters, because these agents are potent stimulants for neutrophil secretion of MPO and H₂O₂. This study may also provide a possible mechanism for the reported in situ NK activity suppression by adherent phagocytic cells during carcinogenesis in both humans and animals.