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J Exp Med. 1991 May 1; 173(5): 1047–1052.
PMCID: PMC2118861

Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer

Abstract

The tumor necrosis factor alpha (TNF-alpha) gene was introduced by retroviral gene transfer into the TNF-alpha-insensitive tumor cell line J558L. Production of 40 pg/ml TNF-alpha by clone J2T12 consistently did not change the growth rate in vitro, but drastically suppressed tumor growth when injected into syngeneic BALB/c mice. Within 2 wk, 90% of the mice inoculated with J558L cells developed a tumor, but none of the mice injected with J2T12 did so. Within the observation period (greater than 3 mo), 60% of the mice inoculated with J2T12 did not develop a tumor. In the other 40% of the mice, tumor manifestation was significantly delayed. Mice injected simultaneously with J2T12 cells and an anti-TNF-alpha monoclonal antibody developed tumors similar to parental J558L cells. Similarly, the tumor-suppressive effects of TNF- alpha were abolished, e.g., by injection of an anti-type 3 complement receptor (CR3) monoclonal antibody that is known to prevent migration of inflammatory cells. These results and the observation of tumor- infiltrating macrophages suggest that lack of tumorigenicity of J2T12 cells is due to the TNF-alpha secretion by the tumor cells and that TNF- alpha acts indirectly by a mechanism that involves chemotactic recruitment and activation of cells, predominantly of macrophages. In contrast, the tumor growth was not affected when, instead of TNF-alpha, interleukin 6 was expressed by J558L cells. Together, our results support the concept of tumor cell-targeted cytokine gene transfer as a tool for cancer treatment, and particularly demonstrate that extremely low doses of TNF-alpha produced by tumor cells are sufficient to inhibit tumor growth without detectable side effects.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Rosenberg SA. Immunotherapy of cancer using interleukin 2: current status and future prospects. Immunol Today. 1988 Feb;9(2):58–62. [PubMed]
  • Russell SJ. Lymphokine gene therapy for cancer. Immunol Today. 1990 Jun;11(6):196–200. [PubMed]
  • Tepper RI, Pattengale PK, Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell. 1989 May 5;57(3):503–512. [PubMed]
  • Li WQ, Diamantstein T, Blankenstein T. Lack of tumorigenicity of interleukin 4 autocrine growing cells seems related to the anti-tumor function of interleukin 4. Mol Immunol. 1990 Dec;27(12):1331–1337. [PubMed]
  • Bubeník J, Símová J, Jandlová T. Immunotherapy of cancer using local administration of lymphoid cells transformed by IL-2 cDNA and constitutively producing IL-2. Immunol Lett. 1990 Feb;23(4):287–292. [PubMed]
  • Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, Karasuyama H, Vogelstein B, Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990 Feb 9;60(3):397–403. [PubMed]
  • Watanabe Y, Kuribayashi K, Miyatake S, Nishihara K, Nakayama E, Taniyama T, Sakata T. Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9456–9460. [PubMed]
  • Beutler B, Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. [PubMed]
  • Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med. 1988 Mar 1;167(3):1067–1085. [PMC free article] [PubMed]
  • Ming WJ, Bersani L, Mantovani A. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J Immunol. 1987 Mar 1;138(5):1469–1474. [PubMed]
  • Urban JL, Shepard HM, Rothstein JL, Sugarman BJ, Schreiber H. Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5233–5237. [PubMed]
  • Feinman R, Henriksen-DeStefano D, Tsujimoto M, Vilcek J. Tumor necrosis factor is an important mediator of tumor cell killing by human monocytes. J Immunol. 1987 Jan 15;138(2):635–640. [PubMed]
  • Oi VT, Morrison SL, Herzenberg LA, Berg P. Immunoglobulin gene expression in transformed lymphoid cells. Proc Natl Acad Sci U S A. 1983 Feb;80(3):825–829. [PubMed]
  • Miller AD, Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986 Aug;6(8):2895–2902. [PMC free article] [PubMed]
  • Mann R, Mulligan RC, Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. [PubMed]
  • Rosen H, Gordon S. Monoclonal antibody to the murine type 3 complement receptor inhibits adhesion of myelomonocytic cells in vitro and inflammatory cell recruitment in vivo. J Exp Med. 1987 Dec 1;166(6):1685–1701. [PMC free article] [PubMed]
  • Fransen L, Müller R, Marmenout A, Tavernier J, Van der Heyden J, Kawashima E, Chollet A, Tizard R, Van Heuverswyn H, Van Vliet A, et al. Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic expression. Nucleic Acids Res. 1985 Jun 25;13(12):4417–4429. [PMC free article] [PubMed]
  • Boulter CA, Wagner EF. A universal retroviral vector for efficient constitutive expression of exogenous genes. Nucleic Acids Res. 1987 Sep 11;15(17):7194–7194. [PMC free article] [PubMed]
  • Flick DA, Gifford GE. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods. 1984 Mar 30;68(1-2):167–175. [PubMed]
  • Van Snick J, Cayphas S, Szikora JP, Renauld JC, Van Roost E, Boon T, Simpson RJ. cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol. 1988 Feb;18(2):193–197. [PubMed]
  • Richter G, Blankenstein T, Diamantstein T. Evolutionary aspects, structure, and expression of the rat interleukin 4 gene. Cytokine. 1990 May;2(3):221–228. [PubMed]
  • Van Snick J, Vink A, Cayphas S, Uyttenhove C. Interleukin-HP1, a T cell-derived hybridoma growth factor that supports the in vitro growth of murine plasmacytomas. J Exp Med. 1987 Mar 1;165(3):641–649. [PMC free article] [PubMed]
  • Ho MK, Springer TA. Mac-1 antigen: quantitative expression in macrophage populations and tissues, and immunofluorescent localization in spleen. J Immunol. 1982 May;128(5):2281–2286. [PubMed]
  • Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984 Feb;32(2):219–229. [PubMed]
  • Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. [PubMed]
  • Lang RA, Burgess AW. Autocrine growth factors and tumourigenic transformation. Immunol Today. 1990 Jul;11(7):244–249. [PubMed]
  • Mulé JJ, McIntosh JK, Jablons DM, Rosenberg SA. Antitumor activity of recombinant interleukin 6 in mice. J Exp Med. 1990 Mar 1;171(3):629–636. [PMC free article] [PubMed]

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