Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1980 Jul 1;152(1):183–197. doi: 10.1084/jem.152.1.183

Role of activated macrophages in antibody-dependent lysis of tumor cells

PMCID: PMC2185907  PMID: 6995552

Abstract

Treatment of mice with Bacille Calmette-Guerin (BCG) or C parvum activates their peritoneal macrophages to release increased amounts of H2O2, and thereby to lyse extracellular tumor cells, in response to a pharmacologic agent, phorbol myristate acetate (PMA) (1-3). In the present study, the same bacterial vaccines activated peritoneal cells to become cytolytic to lymphoma cells sensitized with alloantiserum, in the absence of PMA. Resident peritoneal cells, or those elicited with thioglycollate broth, were ineffective, not only in PMA-induced lysis, but also in antibody-dependent lysis of tumor cells. The cytolytic effect of BCG peritoneal cells toward sensitized tumor cells appeared to be mediated mostly by macrophages. Cytotoxicity was immunologically specific, contact dependent, rapid, and efficient. Phagocytosis of intact tumor cells was not involved. Alloantiserum-dependent cytolysis was specifically blocked by the Fab fragment of a monoclonal antibody directed against the trypsin-resistant macrophage Fc receptor (FcR II). Thus, tumor cells coated with homologous immunoglobulin interact with FcR II on activated macrophages to trigger an extra-cellular cytolytic response.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bast R. C., Jr, Knapp R. C., Mitchell A. K., Thurston J. G., Tucker R. W., Schlossman S. F. Immunotherapy of a murine ovarian carcinoma with Corynebacterium parvum and specific heteroantiserum. I. Activation of peritoneal cells to mediate antibody-dependent cytotoxicity. J Immunol. 1979 Nov;123(5):1945–1951. [PubMed] [Google Scholar]
  2. Boyle M. D., Ormerod M. G. Destruction of allogeneic tumour cells by peritoneal macrophages. Transplantation. 1976 Mar;21(3):242–246. doi: 10.1097/00007890-197603000-00008. [DOI] [PubMed] [Google Scholar]
  3. Clark R. A., Klebanoff S. J. Studies on the mechanism of antibody-dependent polymorphonuclear leukocyte-mediated cytotoxicity. J Immunol. 1977 Oct;119(4):1413–1418. [PubMed] [Google Scholar]
  4. Curnutte J. T., Babior B. M. Biological defense mechanisms. The effect of bacteria and serum on superoxide production by granulocytes. J Clin Invest. 1974 Jun;53(6):1662–1672. doi: 10.1172/JCI107717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Domzig W., Lohmann-Matthes M. L. Antibody-dependent cellular cytotoxicity against tumor cells. II. The promonocyte identified as effector cell. Eur J Immunol. 1979 Apr;9(4):267–272. doi: 10.1002/eji.1830090404. [DOI] [PubMed] [Google Scholar]
  6. Evans R. Phagocytosis of murine lymphoma cells by macrophages. I. Factors affecting in vitro phagocytosis. Immunology. 1971 Jan;20(1):67–74. [PMC free article] [PubMed] [Google Scholar]
  7. GRANGER G. A., WEISER R. S. HOMOGRAFT TARGET CELLS: SPECIFIC DESTRUCTION IN VITRO BY CONTACT INTERACTION WITH IMMUNE MACROPHAGES. Science. 1964 Sep 25;145(3639):1427–1429. doi: 10.1126/science.145.3639.1427. [DOI] [PubMed] [Google Scholar]
  8. Gale R. P., Zighelboim J. Polymorphonuclear leukocytes in antibody-dependent cellular cytotoxicity. J Immunol. 1975 Mar;114(3):1047–1051. [PubMed] [Google Scholar]
  9. Goldstein I. M., Roos D., Kaplan H. B., Weissmann G. Complement and immunoglobulins stimulate superoxide production by human leukocytes independently of phagocytosis. J Clin Invest. 1975 Nov;56(5):1155–1163. doi: 10.1172/JCI108191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Griffin F. M., Jr, Griffin J. A., Leider J. E., Silverstein S. C. Studies on the mechanism of phagocytosis. I. Requirements for circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane. J Exp Med. 1975 Nov 1;142(5):1263–1282. doi: 10.1084/jem.142.5.1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hafeman D. G., Lucas Z. J. Polymorphonuclear leukocyte-mediated, antibody-dependent, cellular cytotoxicity against tumor cells: dependence on oxygen and the respiratory burst. J Immunol. 1979 Jul;123(1):55–62. [PubMed] [Google Scholar]
  12. Haskill J. S., Fett J. W. Possible evidence for antibody-dependent macrophage-mediated cytotoxicity directed against murine adenocarcinoma cells in vivo. J Immunol. 1976 Nov;117(5 PT2):1992–1998. [PubMed] [Google Scholar]
  13. Henson P. M., Oades Z. G. Stimulation of human neutrophils by soluble and insoluble immunoglobulin aggregates. Secretion of granule constituents and increased oxidation of glucose. J Clin Invest. 1975 Oct;56(4):1053–1061. doi: 10.1172/JCI108152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holland P., Holland N. H., Cohn Z. A. The selective inhibition of macrophage phagocytic receptors by anti-membrane antibodies. J Exp Med. 1972 Mar 1;135(3):458–475. doi: 10.1084/jem.135.3.458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Johnston R. B., Jr, Lehmeyer J. E., Guthrie L. A. Generation of superoxide anion and chemiluminescence by human monocytes during phagocytosis and on contact with surface-bound immunoglobulin G. J Exp Med. 1976 Jun 1;143(6):1551–1556. doi: 10.1084/jem.143.6.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jolley G. M., Boyle M. D., Ormerod M. G. The destruction of allogeneic tumour cells by antibody and adherent cells from peritoneal cavities of mice. Cell Immunol. 1976 Mar 15;22(2):262–270. doi: 10.1016/0008-8749(76)90028-9. [DOI] [PubMed] [Google Scholar]
  17. Kiessling R., Klein E., Wigzell H. "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975 Feb;5(2):112–117. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
  18. Kiessling R., Petranyi G., Kärre K., Jondal M., Tracey D., Wigzell H. Killer cells: a functional comparison between natural, immune T-cell and antibody-dependent in vitro systems. J Exp Med. 1976 Apr 1;143(4):772–780. doi: 10.1084/jem.143.4.772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kohl S., Cahall D. L., Walters D. L., Schaffner V. E. Murine antibody-dependent cellular cytotoxicity to herpes simplex virus-infected target cells. J Immunol. 1979 Jul;123(1):25–30. [PubMed] [Google Scholar]
  20. Koren H. S., Anderson S. J., Larrick J. W. In vitro activation of a human macrophage-like cell line. Nature. 1979 May 24;279(5711):328–331. doi: 10.1038/279328a0. [DOI] [PubMed] [Google Scholar]
  21. Levy P. C., Shaw G. M., LoBuglio A. F. Human monocyte, lymphocyte, and granulocyte antibody-dependent cell-mediated cytotoxicity toward tumor cells. I. General characteristics of cytolysis. J Immunol. 1979 Aug;123(2):594–599. [PubMed] [Google Scholar]
  22. Lohmann-Matthes M. L., Domzig W., Taskov H. Antibody-dependent cellular cytotoxicity against tumor cells. I. Cultivated bone marrow-derived macrophages kill tumor targets. Eur J Immunol. 1979 Apr;9(4):261–266. doi: 10.1002/eji.1830090403. [DOI] [PubMed] [Google Scholar]
  23. Macfarlan R. I., Burns W. H., White D. O. Two cytotoxic cells in peritoneal cavity of virus-infected mice: antibody-dependent macrophages and nonspecific killer cells. J Immunol. 1977 Nov;119(5):1569–1574. [PubMed] [Google Scholar]
  24. Mantovani A., Caprioli V., Gritti P., Spreafico F. Human mature macrophages mediate antibody-dependent cellular cytotoxicity on tumour cells. Transplantation. 1977 Oct;24(4):291–293. doi: 10.1097/00007890-197710000-00010. [DOI] [PubMed] [Google Scholar]
  25. Nathan C. F., Asofsky R., Terry W. D. Characterization of the nonphagocytic adherent cell from the peritoneal cavity of normal and BCG-treated mice. J Immunol. 1977 May;118(5):1612–1621. [PubMed] [Google Scholar]
  26. Nathan C. F., Brukner L. H., Silverstein S. C., Cohn Z. A. Extracellular cytolysis by activated macrophages and granulocytes. I. Pharmacologic triggering of effector cells and the release of hydrogen peroxide. J Exp Med. 1979 Jan 1;149(1):84–99. doi: 10.1084/jem.149.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nathan C. F., Root R. K. Hydrogen peroxide release from mouse peritoneal macrophages: dependence on sequential activation and triggering. J Exp Med. 1977 Dec 1;146(6):1648–1662. doi: 10.1084/jem.146.6.1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nathan C. F., Silverstein S. C., Brukner L. H., Cohn Z. A. Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity. J Exp Med. 1979 Jan 1;149(1):100–113. doi: 10.1084/jem.149.1.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nathan C., Cohn Z. Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages. J Exp Med. 1980 Jul 1;152(1):198–208. doi: 10.1084/jem.152.1.198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Newman S. L., Johnston R. B., Jr Role of binding through C3b and IgG in polymorphonuclear neutrophil function: studies with trypsin-generated C3b. J Immunol. 1979 Oct;123(4):1839–1846. [PubMed] [Google Scholar]
  31. Ojo E., Wigzell H. Natural killer cells may be the only cells in normal mouse lymphoid cell populations endowed with cytolytic ability for antibody-coated tumour target cells. Scand J Immunol. 1978 Apr;7(4):297–306. doi: 10.1111/j.1365-3083.1978.tb00457.x. [DOI] [PubMed] [Google Scholar]
  32. Pape G. R., Troye M., Axelsson B., Perlmann P. Simultaneous occurrence of immunoglobulin-dependent and immunoglobulin-independent mechanisms in natural cytotoxicity of human lymphocytes. J Immunol. 1979 Jun;122(6):2251–2260. [PubMed] [Google Scholar]
  33. Pollack S. B., Emmons S. L. Kinetic analysis of human spontaneous cell-mediated cytotoxicity. J Immunol. 1979 Jul;123(1):160–165. [PubMed] [Google Scholar]
  34. Pollack S. B., Nelson K., Grausz J. D. Separation of effector cells mediating antibody-dependent cellular cytotoxicity (ADC) to erythrocyte targets from those mediating ADC to tumor targets. J Immunol. 1976 Apr;116(4):944–946. [PubMed] [Google Scholar]
  35. Rager-Zisman B., Bloom B. R. Immunological destruction of herpes simplex virus I infected cells. Nature. 1974 Oct 11;251(5475):542–543. doi: 10.1038/251542a0. [DOI] [PubMed] [Google Scholar]
  36. Ralph P., Nakoinz I. Antibody-dependent killing of erythrocyte and tumor targets by macrophage-related cell lines: enhancement by PPD and LPS. J Immunol. 1977 Sep;119(3):950–954. [PubMed] [Google Scholar]
  37. Sanderson C. J., Taylor G. A. Antibody-dependent cell-mediated cytotoxicity in the rat. The role of macrophages. Immunology. 1976 Jan;30(1):117–121. [PMC free article] [PubMed] [Google Scholar]
  38. Scornik J. C., Klein P. A. Antibody-dependent lysis of tumor cells in vivo. I. Early lysis of tumor cells. J Natl Cancer Inst. 1978 Oct;61(4):1143–1148. [PubMed] [Google Scholar]
  39. Shin H. S., Kaliss N., Borenstein D., Gately M. K. Antibody-mediated suppression of grafted lymphoma cells. II. Participation of macrophages. J Exp Med. 1972 Aug 1;136(2):375–380. doi: 10.1084/jem.136.2.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tracey D. E., Wolfe S. A., Durdik J. M., Henney C. S. BCG-induced murine effector cells. I. Cytolytic activity in peritoneal exudates: an early response to BCG. J Immunol. 1977 Sep;119(3):1145–1151. [PubMed] [Google Scholar]
  41. Unkeless J. C. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med. 1979 Sep 19;150(3):580–596. doi: 10.1084/jem.150.3.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yamazaki M., Shinoda H., Suzuki Y., Mizuno D. Two-step mechanism of macrophage-mediated tumor lysis in vitro. Gan. 1976 Oct;67(5):741–745. [PubMed] [Google Scholar]
  43. Zighelboim J., Bonavida B., Fahey J. L. Evidence for several cell populations active in antibody dependent cellular cytotoxicity. J Immunol. 1973 Dec;111(6):1737–1742. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES