Tumor Necrosis Factor: A Potent Effector Molecule for Tumor Cell Killing by Activated Macrophages

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 83; no. 14; pp. 5233 - 5237
• Main Authors: Urban, James L., Shepard, H. Michael, Rothstein, Jay L., Sugarman, Barry J., Schreiber, Hans
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-07-1986; National Acad Sciences
• Subjects: Animals; Antibodies; Biological and medical sciences; Cancer; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Drug Resistance; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glycoproteins - pharmacology; Glycoproteins - therapeutic use; Humans; Immunobiology; Lymphotoxin-alpha - pharmacology; Macrophage Activation; Macrophages; Mice; Mice, Inbred C3H; Modulation of the immune response (stimulation, suppression); Natural killer cells; Neoplasms, Experimental - drug therapy; Oxidases; Recombinant Proteins - pharmacology; T lymphocytes; Tumor Necrosis Factor-alpha; Tumor necrosis factors; Tumors; Rodentia; Cytotoxicity; Activation; Cellular immunity; In vitro; In vivo; Vertebrata; Regulation(control); Mammalia; Mouse; Tumor necrosis factor; Animal; Tumor; Inhibition; Tumor cell; Macrophage
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.83.14.5233

Activated macrophages (aMφ ) destroy more effectively cancer cells than normal cells. The mechanism by which macrophages destroy cancer cells is not known. We report here that tumor cells susceptible to aMφ were killed by recombinant (r) tumor necrosis factor type α (TNF-α ), whereas variant tumor cells resistant to aMφ after selection in vitro or in vivo were resistant to killing by rTNF-α . The converse selection for rTNF-α -resistant variants resulted in cells that were also resistant to killing by aMφ . The sensitivity of macrophage-resistant variants was not changed to other tumoricidal cells or soluble mediators, except that the macrophage-resistant variants were also resistant to the effects of another cytotoxic protein, B-cell lymphotoxin, which is structurally related to rTNF-φ . Similar results were obtained regardless of whether short-term or long-term cytotoxic effects of aMφ were measured. Finally, it was shown that killing of tumor cells by murine aMφ was completely inhibited with a polyclonal antibody that neutralizes the effects of murine TNF-α . These results suggest a major role for TNF-α in tumor cell destruction by aMφ in vitro and in vivo.