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Potentiation of antitumor effects of tumor necrosis factor α and interferon γ by macrophage-colony-stimulating factor in a MmB16 melanoma model in mice

  • Original Article
  • Tumor Necrosis Factor α, Interferon γ, Macrophage-Colony-Stimulating Factor, Tumor Immunotherapy
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Abstract

The efficacy of systemic infusion of recombinant human macrophage-colony-stimulating factor (M-CSF) in combination with local treatment with human recombinant tumor necrosis factor (TNF) α and mouse recombinant interferon (IFN) γ was studied in vivo on a subclone of B16 melanoma (MmB16) in mice. Short-term intravenous administration of M-CSF at a dose of 106 units daily had no antitumor effect in vivo. Similarly, local treatment of tumor with TNFα (5 μg daily) did not produce any therapeutic effect. However, simultaneous administration of the same dose of TNFα with IFNγ (1000 units daily) resulted in a synergistic effects manifested by the retardation of tumor growth. Addition of systemic infusion of M-CSF to the local therapy with TNFα and IFNγ induced further augmentation of antitumor efficacy and delayed progression of MmB16 melanoma. The strengthened antitumor effect of combination therapy including M-CSF, TNFα and IFNγ was most probably due to the increased release of monocytes from the bone marrow, their recruitment into the site of tumor growth and subsequent local stimulation of their antitumor activity.

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References

  1. Ampel NM, Wing EJ, Waheed A, Shadduck RK (1986) Stimulatory effects of purified macrophage colony-stimulating factor on murine resident peritoneal macrophages. Cell Immunol 97:344

    PubMed  Google Scholar 

  2. Bigda J, Beletsky I, Brakebusch C, Varfolomeev Y, Engelmann H, Bigda J, Holtmann H, Wallach D (1994) Dual role of the p75 tumor necrosis factor (TNF) receptor in TNF cytotoxicity. J Exp Med 180:445

    PubMed  Google Scholar 

  3. Bock SN, Cameron RB, Kragel P, Mule JJ, Rosenberg SA (1991) Biological and antitumor effects of recombinant human macrophage colony-stimulating factor in mice. Cancer Res 51:2649

    PubMed  Google Scholar 

  4. Botazzi B, Walter S, Govoni D, Colotta F, Mantovani A (1992) Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 148:1280

    PubMed  Google Scholar 

  5. Brouckaert PGG, Leroux-Roels GG, Guisez Y, Tavernier J, Fiers W (1986) In vivo anti-tumor activity of recombinant human and murine TNF, alone and in combination with murine IFN-γ, on a syngeneic murine melanoma. Int J Cancer 38:763

    PubMed  Google Scholar 

  6. Brouckaert P, Everaerdt B, Libert C, Takahashi N, Cauwels A, Fiers W (1993) Strategies to broaden the therapeutic margin of tumor necrosis factor. In: Tumor necrosis factor: molecular and cellular biology and clinical relevance. Karger, Basel, p 226

    Google Scholar 

  7. Celada A, Nathan C (1994) Macrophage activation revisited. Immunol Today 15:100

    PubMed  Google Scholar 

  8. Chen L, Suzuki Y, Wheelock EF (1987) Interferon-γ synergizes with tumor necrosis factor and with interleukin 1 and requires the presence of both monokines to induce antitumor cytotoxic activity in macrophages. J Immunol 139:4096

    PubMed  Google Scholar 

  9. Cole DJ, Sanda MG, Yang JC, Schwartzentruber DJ, Weber J, Ettinghausen SE, Pockaj BA, Kim HI, Levin RD, Pogrebniak HW, Balkissoon J, Fenton RM, DeBarge LR, Kaye J, Rosenberg SA, Parkinson DR (1994) Phase I trial of recombinant human macrophage colony-stimulating factor administered by continuous intravenous infusion in patients with metastatic cancer. J Natl Cancer Inst 86:39

    PubMed  Google Scholar 

  10. Das DK, Stanley ER (1982) Structure-function studies of a colony stimulating factor (CSF-1). J Biol Chem 257:13679

    PubMed  Google Scholar 

  11. Deng W, Thiel B, Tannenbaum CS, Hamilton TA, Stuehr DJ (1993) Synergistic cooperation between T cell lymphokines for induction of the nitric oxide synthase gene in murine peritoneal macrophages. J Immunol 151:322

    PubMed  Google Scholar 

  12. Dong Z, O'Brian CA, Fiedler IJ (1993) Activation of tumoricidal properties in macrophages by lipopolysaccharide requires protein-tyrosine kinase activity. J Leukoc Biol 53:53

    PubMed  Google Scholar 

  13. Dorsch M, Hock H, Kunzendorf U, Diamanstein T, Blankenstein T (1993) Macrophage colony-stimulating factor gene transfer into tumor cells induces macrophage infiltration but not tumor suppression. Eur J Immunol 23:186

    PubMed  Google Scholar 

  14. Fransen L, Heyden J van der, Ruysschaert R, Fiers W (1986) Recombinant tumor necrosis factor: its effect and its synergism with interferon-γ on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 22:419

    PubMed  Google Scholar 

  15. Halenbeck R, Kawasaki E, Wrin J, Koths K (1989) Renaturation and purification of biologically active recombinant human macrophage colony-stimulating factor expressed inE. coli. Biotechnology 7:710

    Google Scholar 

  16. Hamilton JA (1993) Colony stimulating factors, cytokines and monocyte-macrophages — some controversies. Immunol Today 14:18

    PubMed  Google Scholar 

  17. Hieber U, Heim ME (1994) Tumor necrosis factor for the treatment of malignancies. Oncology 51:142

    PubMed  Google Scholar 

  18. Hori K, Ehrke MJ, Mace K, Mihich E (1987) Effect of recombinant tumor necrosis factor on tumoricidal activation of murine macrophages: synergism between tumor necrosis factor and γ-interferon. Cancer Res 47:5868

    PubMed  Google Scholar 

  19. Hume D, Pavli P, Donahue RE, Fiedler IJ (1988) The effect of human recombinant macrophage colony-stimulating factor (CSF-1) on the murine mononuclear phagocyte system in vivo. J Immunol 141:3405

    PubMed  Google Scholar 

  20. Issekutz AC, Issekutz TB (1993) Quantitation and kinetics of blood monocyte migration to acute inflammatory reactions, and IL-1α, tumor necrosis factor-α, and IFN-γ. J Immunol 151:2105

    PubMed  Google Scholar 

  21. Lin HS, Gordon S (1979) Secretion of plasminogen activator by bone marrow-derived mononuclear phagocytes and its enhancement by colony-stimulating factor. J Exp Med 150:231

    PubMed  Google Scholar 

  22. Lu L, Shen R-N, Lin Z-H, Aukerman SL, Ralph P, Broxmeyer HE (1991) Anti-tumor effects of recombinant human macrophage colony stimulating factor, alone or in combination with local irradiation, in mice inoculated with Lewis lung carcinoma cells. Int J Cancer 47:143

    PubMed  Google Scholar 

  23. Motoyoshi K (1994) Macrophage colony-stimulating factor for cancer therapy. Oncology 51:198

    PubMed  Google Scholar 

  24. Nakabo Y, Harakawa N, Yamamoto K, Okuma M, Uno K, Sasada M (1993) Leukemic cell lysis by activated human macrophages: significance of membrane-associated tumor necrosis factor. Jpn J Cancer Res 84:1174

    PubMed  Google Scholar 

  25. Nishimura T, Ohta S, Sato N, Togashi Y, Goto M, Hashimoto Y (1987) Combination tumor-immunotherapy with recombinant tumor necrosis factor and recombinant interleukin 2 in mice. Int J Cancer 40:255

    PubMed  Google Scholar 

  26. Sampson-Johannes A, Carlino JA (1988) Enhancement of human monocyte tumoricidal activity by recombinant M-CSF. J Immunol 141:3680

    PubMed  Google Scholar 

  27. Sodhi A, Suresh A, Singh SM (1993) Effect of interferon-gamma, tumor necrosis factor, interleukin-1 and interleukin-6 on the modulation of anti-tumor responses of bone marrow derived macrophages. Int J Immunopharmacol 15:327

    PubMed  Google Scholar 

  28. Stout RD (1993) Macrophage activation by T cells: cognate and non-cognate signals. Curr Opin Immunol 5:398

    PubMed  Google Scholar 

  29. Talmadge JE (1988) Therapeutic potential of cytokines: a comparison of preclinical and clinical studies. Prog Exp Tumor Res 32:154

    PubMed  Google Scholar 

  30. Ulich TR, Castillo J del, Watson LR, Yin S, Garnick MB (1990) In vivo hematologic effects of recombinant human macrophage colony-stimulating factor. Blood 75:846

    PubMed  Google Scholar 

  31. Vaglini M, Belli F, Ammatuna M, Inglese MG, Manzi R, Prada A, Persiani L, Santinami M, Santoro N, Cascinelli N (1994) Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gammainterferon, and melphalan. Cancer 73:483

    PubMed  Google Scholar 

  32. Wang JM, Griffin JD, Rambaldi A, Chen ZG, Mantorani A (1988) Induction of monocyte migration by recombinant macrophage-colony stimulating factor. J Immunol 141:575

    PubMed  Google Scholar 

  33. Warren MK, Ralph P (1986) Macrophage growth factor, CSF-1, stimulates human monocyte production of interferon, tumor necrosis factor, and colony stimulating activity. J Immunol 137:2281

    PubMed  Google Scholar 

  34. Weiner LM, Li W, Holmes M, Catalano RB, Dovnarsky M, Padavic K, Alpaugh RK (1994) Phase I trial of recombinant macrophage colony-stimulating factor and recombinant γ-interferon: toxicity, monocytosis, and clinical effects. Cancer Res 54:4084

    PubMed  Google Scholar 

  35. Wing EJ, Ampel NM, Waheed A, Shadduck RK (1985) Macrophage colony stimulating factor (M-CSF) enhances the capacity of murine macrophages to secrete oxygen reduction products. J Immunol 135:2052

    PubMed  Google Scholar 

  36. Winkelhake JL, Stampfl S, Zimmerman RJ (1987) Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models. Cancer Res 47:3948

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, Institute of Biostructure, Medical School of Warsaw, ul. Chaŀubińskiego 5, 02-004, Warsaw, Poland

    Witold Lasek, Anna Wańkowicz, Katarzyna Kuc, Wojciech Feleszko, Jakub Golab, Adam Giermasz & Marek Jakóbisiak

  2. Department of Immunology, Central Clinical Hospital, Military School of Medicine, Warsaw, Poland

    Wiesŀaw Wiktor-J/cedrzejczak

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  1. Witold Lasek
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  2. Anna Wańkowicz
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  3. Katarzyna Kuc
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  4. Wojciech Feleszko
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  7. Wiesŀaw Wiktor-J/cedrzejczak
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  8. Marek Jakóbisiak
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Lasek, W., Wańkowicz, A., Kuc, K. et al. Potentiation of antitumor effects of tumor necrosis factor α and interferon γ by macrophage-colony-stimulating factor in a MmB16 melanoma model in mice. Cancer Immunol Immunother 40, 315–321 (1995). https://doi.org/10.1007/BF01519632

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  • DOI: https://doi.org/10.1007/BF01519632

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