Mechanisms of Macrophage-Mediated Tumor Cytolysis

  • M. E. Key
  • L. Hoyer
  • C. Bucana
  • M. G. HannaJr.
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 146)


Important roles have been proposed for both cellular (1,2) and humoral (3–5) immunity in the complex host reaction to neoplastic growth. Killing of syngeneic tumor cells, at least in vitro, can be mediated by many different host cell types either alone or in combination with humoral factors. The mechanisms of tumor cell destruction by macrophages in particular have been studied extensively because of the known tumoricidal properties of macrophages (6–8) and the histological observation that these cells are capable of infiltrating various solid tumors in several different species (9).


Bacillus Calmette Guerin Dextran Sulfate Tumor Cell Killing Tumor Cell Surface Muramyl Dipeptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Haskill, J.S., Hayry, P., and L.A. Radov. Systemic and local immunity in allograft and cancer rejection. Contemp. Top. Immunobiol. 8:107–170 (1978).PubMedCrossRefGoogle Scholar
  2. 2.
    Herberman, R.B., Holder, H.T., Varesio, L., Taniyama, T., Puccetti, P., Kirchner, H., Gerson, J., White, S., Keisari, Y., and J.S. Haskill. Immunologic reactivity of lymphoid cells in tumors. Contemp. Top. Immunobiol. 10:61–78 (1980).Google Scholar
  3. 3.
    Witz, I.P. Tumor-bound immunoglobulins: In situ expressions of humoral Immunity. Adv. Cancer Res. 25:95–141 (1977).PubMedCrossRefGoogle Scholar
  4. 4.
    Von Kleist, S., King, M., and C. Huet. Evidence for membrane- bound antibodies directed against antigens expressed on tumors, Contemp. Top. Immunobiol. 10:177–189 (1980).Google Scholar
  5. 5.
    Shin, H.S. Johnson, R.J., Pasternack, G.R., and J.S. Economou. Mechanisms of tinnor immttnity: The role of antibody and nonimmune effectors. Prog. Allergy 25:163–210 (1978).PubMedGoogle Scholar
  6. 6.
    Fidler, I.J., and A. Raz. The induction of tumoricidal capacities in mouse and rat macrophages by lymphokines. Ljrmphokines 3:345–363 (1981).Google Scholar
  7. 7.
    Evans, R., and P. Alexander. Mechanism of extracellular killing of nucleated mammalian cells by macrophages, “Immunobiology of the Macrophage,” D.S. Nelson, ed. Academic Press, New York, pp. 535–576 (1976).Google Scholar
  8. 8.
    Hibbs, J.B., Jr. Role of macrophages in resistance to cancer. In “Immunologic Aspects of Neoplasia,” M. D. Anderson Hospital and Tumor Institute, Williams and Williams Co., Baltimore, pp. 305–327 (1975).Google Scholar
  9. 9.
    Evans, R. Macrophages in syngeneic animal tumors. Transplantation 14:468–473 (1972).PubMedCrossRefGoogle Scholar
  10. 10.
    Mackaness, G.B. Role of macrophages in host defense mechanisms. In “The Macrophage in Neoplasia,” M.A. Fink, Ed., Academic Press (1976).Google Scholar
  11. 11.
    Haskill, J.S. A micro-colony-inhibition method for quantitation of tumor immtttiity. J. Natl. Cancer Inst. 51:1581–1588 (1973).PubMedGoogle Scholar
  12. 12.
    Zbar, B., Wepsic, H.T., Rapp, H.J., Whang-Peng, J., and T. Borsos. Transplantable hepatomas induced in strain-2 guinea pigs by diethylnitrosamine: characterization by histology, growth, and chromosomes. J. Natl. Cancer Inst. 43:821–831 (1969).PubMedGoogle Scholar
  13. 13.
    Haskill, J.S., Key, M.E., Radov, L.A., Parthenais, E., Korn, J.H., Fett, J.W., Yamamura, Y., DeLustro, F., Vesley, J., and G. Gant. The importance of antibody and macrophages in spontaneous and drug-induced regression of the T1699 mammary adenocarcinoma. J. Reticuloendothel. Soc. 26:417–425 (1979).PubMedGoogle Scholar
  14. 14.
    Hanna, M.G., Jr., Bucana, C., Hobbs, B., and Fidler, I.J. Morphological aspects of tumor cell cytotoxicity by effector cells of the macrophage-histiocyte compartment: In vitro and in vivo studies in BCG-mediated tumor regression. In “The Macrophage in Neoplasia,” M. Fink, Ed., Academic Press, New York, pp. 113–133 (1976).Google Scholar
  15. 15.
    Hibbs, J.B., Jr., Lambert, L.H., Jr., and J.S. Remington. Resistance to murine tumors conferred by chronic infection with intracellular protozoa. Toxoplasma gondii and Besnoitia jellisoni. J. Infect. Dis. 124:587–592 (1971).PubMedCrossRefGoogle Scholar
  16. 16.
    Hibbs, J.R., Jr. Discrimination between neoplastic and nonneoplastic cells in vitro by activated macrophages. J. Natl. Cancer Inst. 53:1487–1492 (1974).PubMedGoogle Scholar
  17. 17.
    Churchill, W.H., Jr., Piessens, W.F., Sulis, C.A., and J.R. David. Macrophages activated as suspension cultures with lymphocyte mediators devoid of antigen become cytotoxic for tumor cells. J. Immunol. 115:781–786 (1975).PubMedGoogle Scholar
  18. 18.
    Plessens, W.F., Churchill, W.H., Jr., and J.R. David. Macrophages activated vitro with lymphocyte mediators kill neoplastic but not normal cells. J. Immunol. 114:293–299 (1975).Google Scholar
  19. 19.
    Ruco, L.P., and M.S. Meitzer. Macrophage activation for tumor cytotoxicity: tumoricidal activity by macrophages from C3H/HeJ mice requires at least two activation stimuli. Cell. Immunol. 41:35–51 (1978).PubMedCrossRefGoogle Scholar
  20. 20.
    Sone, S., and I.J. Fidler. Syngergistic activation by lympho- kines and muramyl dipeptide of tumoricidal properties in rat alveolar macrophages. J. Immunol. 125:2454–2460 (1980).PubMedGoogle Scholar
  21. 21.
    Sone, S., Poste, G., and Fidlef, I.J. Rat alveolar macrophages are susceptible to activation by free and liposome-encapsulated lymphokines. J. Immunol. 124:2197–2202 (1980).PubMedGoogle Scholar
  22. 22.
    Sone, S., and I.J. Fidler. In vitro activation of tumoricidal properties in rat alveolar macrophages by synthetic muramyl dipeptide encapsultated in liposomes. Cell. Immunol. 57:42–50 (1981).PubMedCrossRefGoogle Scholar
  23. 23.
    Hibbs, J.B., Jr. Heterocytolysis by macrophages activated by Bacillus Calmette-Guerin: Lysosome exocytosis into tumor cells Science 184:468–471 (1974).Google Scholar
  24. 24.
    Kramer, J.J., and G.A. Granger. In vitro induction and release of a cell toxin by immime C57/BL6 mouse peritoneal macrophages. Cell. Immunol. 3:88–100 (1972).PubMedCrossRefGoogle Scholar
  25. 25.
    Adams, D.O. Effector mechanisms of cytolytically activated macrophages. I. Secretion of neutral proteases and effect of protease inhibitors. J. Immunol. 124:286–292 (1980).PubMedGoogle Scholar
  26. 26.
    Adams, D.O., Kao, K., Farb, R., and S.V. Pizzo. Effector mechanisms of cytolytically activated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neutral proteases. J. Immunol. 124:293–300 (1980).PubMedGoogle Scholar
  27. 27.
    Fidler, I.J., Sone, S., Fogler, W.E., and Z.L. Barnes. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc. Natl. Acad. Sci. USA 78:1680–1684 (1981).PubMedCrossRefGoogle Scholar
  28. 28.
    Hart, I.R. The selection and characterization of an invasive variant of the B16 melanoma. Am. J. Pathol. 97:587–600 (1979).PubMedGoogle Scholar
  29. 29.
    Fidler, I.J., Raz, A., Fogler, W.E., Kirsh, R., Bugelski, P., and G. Poste. Design of liposomes to improve delivery of mac- rophage-augmenting agents to alveolar macrophages. Cancer Res. 40:4460–4466 (1980).PubMedGoogle Scholar
  30. 30.
    Marino, P.A., and D.O. Mams. Interaction of Bacillus Calmette- Guerin-activated macrophages and neoplastic cells in vitro. I. Conditions of binding and its selectivity. Cell. Inmrnnol. 54: 11–25 (1980).CrossRefGoogle Scholar
  31. 31.
    Marino, P.A., and D.O. Adams. Interaction of Bacillus Calmette- Guerin-activated macropahges and neoplastic cells in vitro. II, The relationship of selective binding to cytolysis. Cell. Immu- nol. 54:26–35 (1980).CrossRefGoogle Scholar
  32. 32.
    Bucana, C., Hoyer, L.C., Hobbs, B., Breesman, S., McDaniel, M., and M.G. Hanna, Jr. Morphological evidence for the translocation of lysosomal organelles from cytotoxic macrophages into the cytoplasm of tumor target cells. Cancer Res. 36:4444–4458. (1976).PubMedGoogle Scholar
  33. 33.
    Evans, R., and P. Alexander. Rendering macrophages specifically cytotoxic by a factor released from immune lymphoid cells. Transplantation 12:227–229 (1971).PubMedCrossRefGoogle Scholar
  34. 34.
    Pearson, G.R. In vitro and in vivo investigations on antibody- dependent cellular cytotoxicity. Cur. Top. Microbiol. Immunol. 80:65–96 (1978).CrossRefGoogle Scholar
  35. 35.
    Johnston, R.B., Jr., Lehmeyer, J.E., and L.A. Guthrie. Generation of superoxide anion and chemiluminescence by human monocytes during phagocytosis and on contact with surface-bound immunoglobulin G. J. Exp. Med. 143:1551–1556 (1976).PubMedCrossRefGoogle Scholar
  36. 36.
    Yamazaki, M., Shinoda, H., Suzuki, Y., and D. Mizuno. Two- step mechanism of macrophage-mediated tumor lysis vitro. Gann. 67:741–745 (1976).PubMedGoogle Scholar
  37. 37.
    Key, M., and J.S. Haskill. Macrophage-mediated antibody- dependent destruction of tumor cells in DBA/2 mice: In vitro identification of an in situ mechanism. J. Natl. Cancer Inst. 66:103–110 (1981).PubMedGoogle Scholar
  38. 38.
    Odartchenko, N., Sordat, B., Pavillard, M., and H. Cottier. Cytokinetic studies on tingible bodies in germinal centers of Peyer’s patches in mice. In “Lymphatic tissue and germinal centers in immune response,” L. Fiore-Donati and M.G. Hanna, Jr., Eds., Plenum Press, New York, pp. 93–100 (1969).CrossRefGoogle Scholar
  39. 39.
    Griffin, P.M., Jr., Griffin, J.A., Leider, J.E., and S.C. Silverstein. Studies on the mechanism of phagocytosis. I. Requirements of circumferential attachment of particle-bound ligands to specific receptors on the macrophage plasma membrane. J. Exp. Med. 142:1263–1282 (1975).PubMedCrossRefGoogle Scholar
  40. 40.
    Kay, M.M.B. Mechanism of removal of senescent cells by human macrophages in vitro. Proc. Natl. Acad. Sci. USA 72:3521–3525 (1975).PubMedCrossRefGoogle Scholar
  41. 41.
    Key, M.E., and J.S. Haskill. Immunohistologic evidence for the role of antibody and macrophages in regression of the murine T1699 mammary adenocarcinoma. Int. J. Cancer 28:225- 236 (1981).Google Scholar
  42. 42.
    Hanna, M.G., Jr., Snodgrass, M.J., Zbar, B., and H.J. Rapp. Histopathology of tumor regression after intralesional injection of Mycobacterium bovis. IV. Development of immunity to tumor cells and BCG. J. Natl. Cancer Inst. 51:1897–1908 (1973).PubMedGoogle Scholar
  43. 43.
    Fidler, I.J., Budmen, M.B., and M.G. Hanna, Jr. Characterization of vitro reactivity by BCG-treated guinea pigs on syngeneic Line-10 hepatocarcinoma. Cancer Immunol. Immunother. 1:179–186 (1979).CrossRefGoogle Scholar
  44. 44.
    Henson, P.M., and Z.G. Oades. Stimulation of human neutro- phlls by soluble and Insoluble immunoglobulin aggregates: Secretion of granule constituents and increased oxidation of glucose. J. Clin. Invest. 56:1053–1059 (1975).PubMedCrossRefGoogle Scholar
  45. 45.
    Carr, I., Carr, J., Trew, J.A., Lobo, A., and P.K. Chattopadhyay. Lysozyme production by a granuloma in vivo: Output in blood and lymph in relation to ultra struct ure and immunochemistry. J. Pathol. 132:105–119 (1980).PubMedCrossRefGoogle Scholar
  46. 46.
    Cohn, Z.A. Macrophage physiology. Federation Proc. 34:1725–1729 (1975).Google Scholar
  47. 47.
    Gallin, J.I., Wright, D.E., and E. Schiffmann. Role of secretory events in modulating human neutrophil Chemotaxis. J. Clin. Invest. 62:1364–1374 (1978).PubMedCrossRefGoogle Scholar
  48. 48.
    Haskill, J.S. ADCC effector cells in a murine adenocarcinoma. I. Evidence for blood-borne bone-marrow-derived monocytes. Int. J. Cancer 20:432–440 (1977).PubMedCrossRefGoogle Scholar
  49. 49.
    Snodgrass, M.J., and M.G. Hanna, Jr. Ultrastructural studies of histiocyte-tumor cell interactions during tumor regression after intralesional injection of Mycobacterium bovis. Cancer Res. 33:701–716 (1973).PubMedGoogle Scholar
  50. 50.
    Hanna, M.G., Jr., Zbar, B., and H.J. Rapp. Histopathology of tumor regression after intralesional injectional of Mycobacterium bovis. I. Tumor growth and metastasis. J. Natl. Cancer Inst. 48:1441–1455 (1972).PubMedGoogle Scholar
  51. 51.
    Nicolson, G.L. Transmembrane control of the receptors on normal and tumor cells and some surface changes associated with transformation and malignancy. Biochim. Biophys. Acta 458:1–72 (1976).PubMedGoogle Scholar
  52. 52.
    Amos, D.B. Possible relationships between cytotoxic effects of isoantibody and host cell function. Ann. N.Y. Acad. Sci. 87:273–292 (1960).PubMedCrossRefGoogle Scholar
  53. 53.
    Bennett, B. Phagocytosis of mouse tumor cells in vitro by various homologous and heterologous cells. J. Immunol. 95: 80–86 (1965).PubMedGoogle Scholar
  54. 54.
    The, H.T., Eibergen, R., Lamberts, H.B., Oldhoff, J., Ploeg, E., Schrafford-Keops, H., and H.O. Neiweg. Immune phagocytosis in vivo of human malignant melanoma cells. Acta Med. Scand. 192:141–144 (1972).PubMedCrossRefGoogle Scholar
  55. 55.
    Walker, W.S. Mediation of macrophage cytolytic and phagocytic activities by antibodies of different classes and class-specific Fc-receptors. J. Immunol. 119:367–373 (1977).PubMedGoogle Scholar
  56. 56.
    Werb, Z., and Z.A. Cohn. Plasma membrane synthesis in the macrophage following phagocytosis of polystyrene latex particles. J. Biol. Chem. 247:2439–2446 (1972).PubMedGoogle Scholar
  57. 57.
    Karnovsky, M.L., and J.K. Lazdins. Biochemical criteria for activated macrophages. J. Immunol. 121:809–813 (1978).PubMedGoogle Scholar
  58. 58.
    Saito, K., and E. Suter. Lysosomal acid hydrolases in mice infected with BCG. J. Exp. Med. 121:727–749 (1965).PubMedCrossRefGoogle Scholar
  59. 59.
    Hard, G.C. Some biochemical aspects of the immune macrophage. Br. J. Exp. Pathol. 51:97–105 (1970).Google Scholar
  60. 60.
    Karnovsky, M.L., Lazdins, J., and S.R. Simmons. Metabolism of activated mononuclear phagocytes at rest and during phagocytosis. “Nonuclear Phagocytes in Immunity, Infection, and Pathology,” R. Van Furth, Ed., Blackwell Scientific Publications, Oxford, Edinburgh, and Melbourne, pp. 423–439 (1975).Google Scholar
  61. 61.
    Riisgaard, S., Bennedsen, J., and J.M. Rhodes. In vitro studies on normal, stimulated and immunologically activated mouse macrophages. I. Oxidation of 1-C-glucose by macrophages in monolayer cultures. Acta Pathol. Microbiol. Scand. [C]. 85:233–238 (1977).Google Scholar
  62. 62.
    Karnovsky, M.L., Lazdins, J., Drath, D., and A. Harper. Biochemical characteristics of activated macrophages. Ann. N.Y. Acad. Sci. 256:266–274 (1975).PubMedCrossRefGoogle Scholar
  63. 63.
    Stadecker, M.J., Calderon, J., Karnovsky, M.L., and E.R. Unanue. S5mthesis and release of thymidine by macrophages. J. Immunol. 119:1738–1743 (1977).PubMedGoogle Scholar
  64. 64.
    Currie, G.A., and C. Basham. Differential arginine dependence and the selective cytotoxic effects of activated macrophages for malignant cells in vitro. Br. J. Cancer 38:653–659 (1978).PubMedCrossRefGoogle Scholar
  65. 65.
    Ferluga, J., Schorlemmer, H.J., Baptista, L.C., and A.C. Allison. Production of the complement cleavage product, C3a, by activated macrophages and its tumorolytic effects. Clin. Exp. Immunol. 31:512–517 (1978).PubMedGoogle Scholar
  66. 66.
    Clark, R.A., Klebanoff, S.J., Einstein, A.B., and A. Fefer. Peroxidase-H202-halide system: Cytotoxic effect on mammalian tumor cells. Blood 45:161–170 (1975).PubMedGoogle Scholar
  67. 67.
    Osserman, E.F., Klockars, M., Halper, J., and R.S. Fischel. Effects of lysozyme on normal and transformed mammalian cells. Nature 243:331–225 (1973).PubMedCrossRefGoogle Scholar
  68. 68.
    Nathan, C.F., Brukner, L.H., Silverstein, S.C., and Z.A. Cohn. Extracellular cytolysis by activated macrophages and granulocytes. I. Pharmacologic triggering of effector cells and the release of hydrogen peroxide. J. Exp. Med. 149:84–99 (1979).PubMedCrossRefGoogle Scholar
  69. 69.
    Babior, B.M. Oxygen-dependent microbial killing by phagocytes. N. Engl. J. Med. 298:659–668 (1978).PubMedCrossRefGoogle Scholar
  70. 70.
    Sorrell, T.C., Lehrer, R.I., and M.J. Cline. Mechanism of nonspecific macrophage-mediated cytotoxicity: Evidence for lack of dependence upon oxygen. J. Immunol. 120:347–352 (1978).PubMedGoogle Scholar
  71. 71.
    Johnson, R.B., Jr., Keele, B.B., Jr., and H.P. Mlsra. The role of superoxide anion generation in phagocytic bactericidal activity: studies with normal and chronic granulomatous disease leukocytes. J. Clin. Invest. 55:1357–1372 (1975).CrossRefGoogle Scholar
  72. 72.
    Ruco, L.P., and M.S. Meitzer. Macrophage activation for tumor cytotoxicity: Induction of tumoricidal macrophages by super- natants of ppd-stimulated Bacillus Calme11e-Guerin-immune spleen cell cultures. J. Immunol. 119:889–896 (1977).PubMedGoogle Scholar
  73. 73.
    Hafeman, D.G., and Z.J. Lucas. Polymorphonuclear leukocyte- mediated, antibody-dependent, cellular cytotoxicity against tumor cells: Dependence on oxygen and the respiratory burst. J. Immunol. 123:55–62 (1979).PubMedGoogle Scholar
  74. 74.
    Nathan, C., and Z. Cohn. Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages. J. Exp. Med. 152:198–208 (1980).PubMedCrossRefGoogle Scholar
  75. 75.
    Ifothan, C., Brukner, L., Kaplan, G., Unkeless, J., and Z. Cohn. Role of activated macrophages in antibody-dependent lysis of tumor cells. J. Exp. Ifed. 152:183–197 (1980).CrossRefGoogle Scholar
  76. 76.
    Kitagawa, S., Takaku, F., and S. Sakamoto. Evidence that proteases are involved in superoxide production by human polymorphonuclear leukocytes and monocytes. J. Clin. Invest. 65: 74–81 (1980).PubMedCrossRefGoogle Scholar
  77. 77.
    Evans, R., Booth, C.G., and F. Spencer. Lack of correlation between in vivo rejection of syngeneic fibrosarcomas and nonspecific macrophage cytotoxicity. Br. J. Cancer 38:583–590 (1978).PubMedCrossRefGoogle Scholar
  78. 78.
    Mantovani, A., Polentarutti, N., Peri, G., Shavit, Z., Vecchi, A., Bolis, G., and C. Mangioni. Cytotoxocity on tumor cells of peripheral blood monocytes and tumor-associated macrophages in patients with ascites ovarian tumors. J. Natl. Cancer Inst. 64:1307–1315 (1980).PubMedGoogle Scholar
  79. 79.
    Vose, B.M. Cytotoxicity of adherent cells associated with some human tumors and lung tissues. Cancer Immunol. Immuno- ther. 5:173–179 (1978).Google Scholar
  80. 80.
    Russell, S.W., and C.G. Cochrane. The cellular events associated with regression and progression of murine (Moloney) sarcoma. Int. J. Cancer 13:54–63 (1974).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • M. E. Key
    • 1
  • L. Hoyer
    • 1
  • C. Bucana
    • 1
  • M. G. HannaJr.
    • 1
  1. 1.Cancer Metastasis and Treatment Laboratory, Cancer Research FacilityNCI-FrederickFrederickUSA

Personalised recommendations