Skip to main content
SpringerLink
Log in

Induction of antitumor immunity and treatment of preestablished tumor by interleukin-6-gene-transfected melanoma cells combined with low-dose interleukin-2

  • Original Paper
  • Experimental Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Transfer of cytokine genes into tumor cells has proven a valuable approach for cancer treatment. In order to generate a more effective cancer vaccine, we transfected the human interleukin-6 (IL-6) gene into B16 melanoma cells. A B16 cell clone secreting the highest level of IL-6 was obtained by G418-resistant selection, limiting dilution and IL-6 assay. The IL-6-gene-transfected tumor cells exhibited in vitro growth inhibition, reduced tumorigenicity and decreased metastatic competence. After immunization with the inactivated IL-6-gene-transfected vaccine, the murine cytotoxic T lymphocyte activity, natural killer activity and lymphokine-activated killer activity increased markedly. After treatment with the vaccine, the tumorbearing mice showed significant growth inhibition of subcutaneous tumor, reduction in pulmonary metastases and extension of survival time. The above therapeutic effect was better when low-dose IL-2 was administered simultaneously, although this dosage of IL-2 had no in vivo antitumor effect. These data demonstrated that IL-6-gene-transfected cancer vaccine has a potent antitumor effect via efficient induction of antitumor immunity, and a better therapeutic effect could be achieved when the vaccine is combined with lowdose IL-2 as adjuvant.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

IL :

interleukin

NK :

natural killer

LAK :

lymphokine-activated killer

CTL :

cytotoxic T lymphocytes

References

  • Baroja ML, Ceuppens JL, Damme JV, Billiau A (1988) Cooperation between an anti-T cell (anti-CD28) monoclonal antibody and monocyte-produced IL-6 in the induction of T cell responsiveness to IL-2. J Immunol 141:1502–1507

    PubMed  Google Scholar 

  • Blankenstein T, Qin Z, Überla K, Müller W, Rosen H, Volk HD, Diamantstein T (1991) Tumor suppression after tumor cell-targeted tumor necrosis factor α gene transfer. J Exp Med 173:1047–1052

    PubMed  Google Scholar 

  • Caligiuri MA, Murray C, Soiffer FJ, Klumpp TR, Seiden M, Cochran K, Cameron C, Ish C, Buchanan L, Perillo D, Smith K, Ritz J (1991) Extended continuous infusion of low-dose recombinant interleukin-2 in advanced cancer prolonged immunomodulation without significant toxicity. J Clin Oncol 9:2110–2119

    PubMed  Google Scholar 

  • Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, Schow P, Ross ME, Klumpp TR, Soiffer RJ, Smith KA, Ritz J (1993) Selective modulation of human antural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest 91:123–132

    PubMed  Google Scholar 

  • Colombo MP, Forni G (1994) Cytokine gene transfer into tumor inhibition and tumor therapy: where are we now? Immunol Today 15:48–51

    PubMed  Google Scholar 

  • Dansky-Ullmann C, Schlom J, Greiner JW (1992) Interleukin-6 increases carcinoembryonic antigen and histocompatibility leukocyte antigen expression on the surface of human colorectal carcinoma cells. J Immunother 12:231–241

    PubMed  Google Scholar 

  • Dougherty GJ, Thacker JD, Lavey RS, Belldegrun A, McBride WH (1994) Inhibitory effect of locally produced and exogenous interleukin-6 on tumor growth in vivo. Cancer Immunol Immunother 38:339–345

    PubMed  Google Scholar 

  • Harada M, Matsuzaki G, Shinomiya K, Kurasawa S, Ito O, Okamoto T, Takenoyama M, Sumitika H, Nishimura Y, Nomoto K (1994) Generation of tumor-specific cytotoxic T lymphocytes in vivo by combined treatment with inactivated tumor cells and recombinant interleukin-2. Cancer Immunol Immunother 38:332–338

    PubMed  Google Scholar 

  • Karasuyama H, Melchers F (1988) Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4, or 5, using modified cDNA expression vectors. Eur J Immunol 18:97–104

    PubMed  Google Scholar 

  • Katz A, Shulman LM, Revel M, Feldman M, Eisenbach L (1993a) Combined therapy with IL-6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas. Int J Cancer 53:812–818

    PubMed  Google Scholar 

  • Katz A, Shulman LM, Porgador A, Revel M, Feldman M, Eisenbach L (1993b) Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy. J Immunother 13:98–109

    PubMed  Google Scholar 

  • Kishimoto T (1989) The biology of interleukin-6. Blood 74:1–10

    PubMed  Google Scholar 

  • Lindemann A, Brossart P, Höffken K, Flasshove M, Voliotis D, Diehl V, Kulmburg P, Wagner H, Mertelsmann R (1994) Serum cytokine levels in cancer patients treated with different schedules of ultra-low-dose interleukin-2. J Immunother 15:225–230

    Google Scholar 

  • Lorré K, Kamme JV, Verwilghen J, Baroja ML, Ceuppens JL (1990) IL-6 is an accessory signal in the alternative CD2-mediated pathway of T cell activation. J Immunol 144:4681–4687

    PubMed  Google Scholar 

  • Luger TA, Krutmann J, Kirnbauer R, Urbanski A, Schwarz H, Klappacher G, Köck A, Micksche M, Malejczyk J, Schauer E, May LT, Sehgal PB (1989) IFN-β2/IL-6 augments the activity of human natural killer cells. J Immunol 143:1206–1209

    PubMed  Google Scholar 

  • Maas RA, Dullens HFJ, Otter WD (1993) Interleukin-2 in cancer treatment: disappointing or (still) promising? A review. Cancer Immunol Immunother 36:141–148

    PubMed  Google Scholar 

  • McAdam AJ, Felcher A, Woods ML, Pulaski BA, Hutter ED, Frelinger JG, Lord EM (1994) Transfection of transforming growth factor-β producing tumor EMT6 with interleukin-2 elicits tumor rejection and tumor reactive cytotoxic T-lymphocytes. J Immunother 15:155–164

    Google Scholar 

  • Meuer SC, Dumann H, Meyer zum Buschenfelde K-H, Kohler H (1989) Low-dose interleukin-2 induces systemic immune responses against HBsAg in immunodeficient non-responders to hepatitis B vaccination. Lancet I 15–17

    Google Scholar 

  • Mulé JJ, McIntosh JK, Jablons DM, Rosenberg SA (1990) Antitumor activity of recombinant interleukin-6 in mice. J Exp Med 171:629–636

    PubMed  Google Scholar 

  • Mulé JJ, Custer MC, Travis WD, Rosenberg SA (1992) Cellular mechanisms of antitumor activity of recombinant IL-6 in mice. J Immunol 148:2622–2629

    PubMed  Google Scholar 

  • Mullen CA, Coale MM, Levy AT, Stetler-Stevenson WG, Liotta LA, Brandt S, Blaese RM (1992) Fibrosarcoma cells transduced with IL-6 gene exhibit reduced tumorigenicity, increased immunogenicity and decreased metastatic potential. Cancer Res 52:6020–6024

    PubMed  Google Scholar 

  • Musso T, Espinoza-Delgado I, Pulkki K, Gusella GL, Longo DL, Varcsio L (1992) IL-2 induces IL-6 production in human monocytes. J Immunol 148:795–800

    PubMed  Google Scholar 

  • Ohe Y, Podack ER, Olsen KJ, Miyahara Y, Miura K, Saito H, Koishihara Y, Ohsugi Y, Ohira T, Nishio K, Saijo N (1993) Interleukin-6 cDNA transfected Lewis lung carcinoma cells show unaltered net tumour growth rate but cause weight loss and shorten survival in syngenic mice. Br J Cancer 67:939–944

    PubMed  Google Scholar 

  • Porgador A, Tzehoval E, Katz A, Vadai E, Revel M, Feldman M, Eisenbach L (1992) Interleukin-6 gene transfection into Lewis lung carcinoma tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. Cancer Res 52:3679–3686

    PubMed  Google Scholar 

  • Salvadori S, Rosenthal FM, Cronin K, Gansbacher B, Zier KS (1993) Tumor-bearing animals contain suppressed antitumor effectors the function of which can be unmasked by IL-2. J Immunother 14:216–220

    PubMed  Google Scholar 

  • Smyth MJ, Ortaldo JR (1991) Comparison of the effect of IL-2 and IL-6 on the lytic activity of purified human peripheral blood large granular lymphocytes. J Immunol 146:1380–1384

    PubMed  Google Scholar 

  • Soiffer RJ, Murray C, Cochran K, Cameron C, Wang E, Schow PW, Daley JF, Ritz J (1992) Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood 79:517–526

    PubMed  Google Scholar 

  • Soiffer RJ, Murray C, Gonin R, Ritz J (1994) Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation. Blood 84:964–971

    PubMed  Google Scholar 

  • Sun WH, Kreisle RA, Phillips AW, Ershler WB (1992) In vivo and in vitro characteristics of interleukin-6-transfected B16 melanoma cells. Cancer Res 52:5412–5415

    PubMed  Google Scholar 

  • Tosato G, Pike SA (1988) Interferon-β2/interleukin-6 is a co-stimulant for human T lymphocytes. J Immunol 141:1556–1562

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology, Second Military Medical University, 800 Xiang Yin Road, 200433, Shanghai, P.R. China

    Xuetao Cao, Weiping Zhang, Shen Gu, Yizhi Yu, Qun Tao & Tianxing Ye

Authors
  1. Xuetao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weiping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shen Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yizhi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qun Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tianxing Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Research supported by the National Natural Science Foundation of China (grant: 39421009)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cao, X., Zhang, W., Gu, S. et al. Induction of antitumor immunity and treatment of preestablished tumor by interleukin-6-gene-transfected melanoma cells combined with low-dose interleukin-2. J Cancer Res Clin Oncol 121, 721–728 (1995). https://doi.org/10.1007/BF01213318

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01213318

Key words

Search

Navigation