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Mechanisms of macrophage cytotoxicity in IL-2 and IL-12 mediated tumour regression

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Abstract

IL-2 and IL-12 are promising anti-tumour agents. However, little attention has been paid to the role of macrophages during IL-2/IL-12 mediated tumour rejection. We studied the role of macrophages during IL-2/IL-12 mediated tumour rejection in DBA/2 mice bearing syngeneic SL2 lymphoma. Local treatment with IL-2 and IL-12 cured 85% of mice with severe metastasised tumour load. In vivo depletion studies showed that macrophages were required for the anti-tumour effect of IL-2 and IL-12. Macrophages could kill tumour cells both non-specifically and by antibody-dependent cellular cytotoxicity (ADCC). Treatment with IL-2, IL-12 or IL-2/IL-12 enhanced production of specific IgG1 immunoglobulins, while treatment with IL-12 and IL-2/IL-12 additionally induced IgG2a production. FcγRII and/or III were essential for ADCC expression after treatment with IL-2 and IL-12. These data show for the first time the essential role of macrophages during IL-2/IL-12 mediated tumour rejection and also suggest that IL-2 and IL-12 act via different mechanisms.

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References

  1. Banchereau J, Briere F, Liu YJ, Rousset F (1994) Molecular control of B lymphocyte growth and differentiation. Stem Cells 12:278

    CAS  PubMed  Google Scholar 

  2. Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254

    Article  CAS  PubMed  Google Scholar 

  3. Claassen I, Van Rooijen N, Claassen E (1990) A new method for removal of mononuclear phagocytes from heterogenous cell populations 'in vitro', using the liposome-mediated macrophage 'suicide' technique. J Immunol Methods 134:153

    Article  CAS  PubMed  Google Scholar 

  4. De Weger RA, Wilbrink B, Moberts RM, Mans D, Oskam R, Den Otter W (1987) Immune reactivity in SL2 lymphoma-bearing mice compared with SL2-immunized mice. Cancer Immunol Immunother 24:25

    PubMed  Google Scholar 

  5. Dijstelbloem HM, van de Winkel JG, Kallenberg CG (2001) Inflammation in autoimmunity: receptors for IgG revisited. Trends Immunol 22:510

    Article  CAS  PubMed  Google Scholar 

  6. Espinoza-Delgado I, Bosco MC, Musso T, Gusella GL, Longo DL, Varesio L (1995) Interleukin-2 and human monocyte activation. J Leukoc Biol 57:13

    CAS  PubMed  Google Scholar 

  7. Espinoza-Delgado I, Longo DL, Gusella GL, Varesio L (1990) IL-2 enhances c-fms expression in human monocytes. J Immunol 145:1137

    CAS  PubMed  Google Scholar 

  8. Gollob JA, Schnipper CP, Murphy EA, Ritz J, Frank DA (1999) The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation. J Immunol 162:4472

    CAS  PubMed  Google Scholar 

  9. Grohmann U, Belladonna ML, Vacca C, Bianchi R, Fallarino F, Orabona C, Fioretti MC, Puccetti P (2001) Positive regulatory role of IL-12 in macrophages and modulation by IFN-gamma. J Immunol 167:221

    CAS  PubMed  Google Scholar 

  10. Ha SJ, Lee SB, Kim CM, Shin HS, Sung YC (1998) Rapid recruitment of macrophages in interleukin-12-mediated tumour regression. Immunology 95:156

    CAS  PubMed  Google Scholar 

  11. Hiraki A, Kiura K, Yamane H, Nogami N, Tabata M, Takigawa N, Ueoka H, Tanimoto M, Harada M (2002) Interleukin-12 augments cytolytic activity of peripheral blood mononuclear cells against autologous lung cancer cells in combination with IL-2. Lung Cancer 35:329

    Article  PubMed  Google Scholar 

  12. Jackson PG, Evans SR (2000) Intraperitoneal macrophages and tumor immunity: a review. J Surg Oncol 75:146

    Article  CAS  PubMed  Google Scholar 

  13. Kovacs EJ, Brock B, Varesio L, Young HA (1989) IL-2 induction of IL-1 beta mRNA expression in monocytes. Regulation by agents that block second messenger pathways. J Immunol 143:3532

    CAS  PubMed  Google Scholar 

  14. Maas RA, Dullens HF, De Jong WH, Den Otter W (1989) Immunotherapy of mice with a large burden of disseminated lymphoma with low-dose interleukin 2. Cancer Res 49:7037

    CAS  PubMed  Google Scholar 

  15. Metzger DW, Buchanan JM, Collins JT, Lester TL, Murray KS, Van Cleave VH (1996) Enhancement of humoral immunity by interleukin-12. Ann N Y Acad Sci 795:100

    CAS  Google Scholar 

  16. Metzger DW, McNutt RM, Collins JT, Buchanan JM, Van Cleave VH, Dunnick WA (1997) Interleukin-12 acts as an adjuvant for humoral immunity through interferon-gamma-dependent and -independent mechanisms. Eur J Immunol 27:1958

    CAS  PubMed  Google Scholar 

  17. Morris SC, Madden KB, Adamovicz JJ, Gause WC, Hubbard BR, Gately MK (1994) Effects of IL-12 on in vivo cytokine gene expression and Ig isotype selection. J Immunol 152:1047

    CAS  PubMed  Google Scholar 

  18. Munder M, Mallo M, Eichmann K, Modolell M (1998) Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med 187:2103

    CAS  PubMed  Google Scholar 

  19. Philip R (1988) Cytolysis of tumor necrosis factor (TNF)-resistant tumor targets. Differential cytotoxicity of monocytes activated by the interferons, IL-2, and TNF. J Immunol 140:1345

    CAS  PubMed  Google Scholar 

  20. Ravetch, JV, Bolland S (2001) IgG Fc receptors. Annu Rev Immunol 19:275

    CAS  PubMed  Google Scholar 

  21. Ryffel B (1997) Interleukin-12: role of interferon-gamma in IL-12 adverse effects. Clin Immunol Immunopathol 83:18

    Article  CAS  PubMed  Google Scholar 

  22. Van Rooijen N, Sanders A (1994) Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods 174:83

    Article  PubMed  Google Scholar 

  23. Wahl SM, McCartney-Francis N, Hunt DA, Smith PD, Wahl LM, Katona IM (1987) Monocyte interleukin 2 receptor gene expression and interleukin 2 augmentation of microbicidal activity. J Immunol 139:1342

    CAS  PubMed  Google Scholar 

  24. Wigginton JM, Gruys E, Geiselhart L, Subleski J, Komschlies KL, Park JW, Wiltrout TA, Nagashima K, Back TC, Wiltrout RH (2001) IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Invest 108:51

    Article  CAS  PubMed  Google Scholar 

  25. Wigginton JM, Komschlies KL, Back TC, Franco JL, Brunda MJ, Wiltrout RH (1996) Administration of interleukin 12 with pulse interleukin 2 and the rapid and complete eradication of murine renal carcinoma. J Natl Cancer Inst 88:38

    CAS  PubMed  Google Scholar 

  26. Wigginton JM, Komschlies KL, Green JE, Cox GW, Jorcyk CL, Back TC, Franco JL, Brunda MJ, Wiltrout RH (1996) Evaluation of the antitumor activity of the interleukin-12/pulse interleukin-2 combination. Ann N Y Acad Sci 795:434

    CAS  PubMed  Google Scholar 

  27. Wigginton JM, Kuhns DB, Back TC, Brunda MJ, Wiltrout RH, Cox GW (1996) Interleukin 12 primes macrophages for nitric oxide production in vivo and restores depressed nitric oxide production by macrophages from tumor-bearing mice: implications for the antitumor activity of interleukin 12 and/or interleukin 2. Cancer Res 56:1131

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to Chiron (Amsterdam, The Netherlands) for providing IL-2 and to the Genetics Institute (Mass., USA) for providing IL-12. Cl2MDP (clodronate) was a gift of Roche Diagnostics GmbH, Mannheim, Germany.

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Authors and Affiliations

  1. Department of Biochemistry, Cell Biology and Histology, Utrecht University, Yalelaan 2, 3584 CM, Utrecht, The Netherlands

    Agnieszka Masztalerz & Willem Den Otter

  2. Departments of Infectious Diseases and Immunology and Biopharmaceutics, Utrecht University, Utrecht, The Netherlands

    Linda A. Everse

  3. Department of Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands

    Nico Van Rooijen

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  1. Agnieszka Masztalerz
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  2. Nico Van Rooijen
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  3. Willem Den Otter
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  4. Linda A. Everse
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Correspondence to Agnieszka Masztalerz.

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Masztalerz, A., Van Rooijen, N., Den Otter, W. et al. Mechanisms of macrophage cytotoxicity in IL-2 and IL-12 mediated tumour regression. Cancer Immunol Immunother 52, 235–242 (2003). https://doi.org/10.1007/s00262-003-0381-z

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  • DOI: https://doi.org/10.1007/s00262-003-0381-z

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