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Lysis of Tumor Cells by Human Blood Monocytes by a Mechanism Independent of Activation of the Oxidative Burst¹

Laboratory of Molecular Immunoregulation, Biological Response Modifiers Program, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [E. S. K., L. M. C., E. B., R. Z.], and Laboratory of Clinical Investigations, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20205 [J. I. G.]

Tumorilytic human blood monocytes recognize and destroy neoplastic cells by a mechanism that is nonphagocytic and requires cell-to-cell contact. The mechanism of cytolysis subsequent to binding is controversial. Release of reactive oxygen intermediates by activated rodent macrophages has been suggested as an important mechanism for tumor cell lysis in some short-term cytotoxicity assays. We examined whether oxygen intermediates are also responsible for mediating the lysis of adherent human tumor cells in a long-term (72-h) tumoricidal assay. Human blood monocytes were incubated with medium, concanavalin A-stimulated lymphokine [macrophage-activating factor (MAF)], lipopolysaccharide endotoxin, or human recombinant interferon for 24 h prior to the addition of [¹²⁵I]iododeoxyuridine-labeled A375 melanoma cells. The following evidence indicated that monocyte-mediated tumor cell lysis was independent of superoxide anion (O₂^-) and H₂O₂ production: (a) although human blood monocytes incubated for 24 h with interferon produced twice as much O₂^- as control or MAF-treated monocytes, interferon did not activate monocyte tumoricidal activity unless combined with lipopolysaccharide endotoxin, 0.2 ng/ml or more; (b) incubating the monocytes with 10 nM phorbol myristate acetate for 0.5 h stimulated O₂^- production but no cytotoxicity; (c) the cytolytic activity of MAF-treated monocytes was not decreased in the presence of catalase or superoxide dismutase; and (d) finally, peripheral blood monocytes were isolated from six patients with chronic granulomatous disease, activated by MAF or lipopolysaccharide endotoxin, and then assayed for tumoricidal activity. While these activated chronic granulomatous disease monocytes did not produce O₂^- or H₂O₂, tumor cell lysis was normal in all six patients. Hence, lysis of tumor cells in a 72-h assay is not dependent upon the generation of O₂^- and/or H₂O₂ and is intact in chronic granulomatous disease monocytes.

¹ Based on work for which E. S. Kleinerman received the Young Investigator Award in reticuloendothelial system research. Presented at the 21st National Meeting of the Reticuloendothelial Society, 1984, Montreal, Canada.

² To whom requests for reprints should be addressed, at Department of Cell Biology, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Drive, HMB 173, Houston, TX 77030.

Received 10/24/84. Revised 1/15/85. Accepted 1/30/85.