Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice

Eur J Immunol. 2000 Jul;30(7):1957-66. doi: 10.1002/1521-4141(200007)30:7<1957::AID-IMMU1957>3.0.CO;2-7.

Abstract

The response of lymphokine-activated killer (LAK) and natural killer (NK) cells from mice lacking tumor necrosis factor-alpha (TNF-alpha-/- mice) was impaired in cytotoxicity assays against various tumor cell targets. Furthermore, allogeneic cytotoxic T lymphocyte (CTL) responses were also impaired as compared to TNF-alpha+/+ littermates (control mice). Cytotoxicity was restored both upon in vitro incubation of TNF-alpha-/- lymphocytes with recombinant TNF-alpha (rTNF-alpha) or upon in vivo treatment of TNF-alpha-/- mice with rTNF-alpha. Using combinations of monoclonal antibodies we were able to show that TNF-alpha-/- effector lymphocytes exhibit both perforin- and Fas ligand-based cytotoxicity. Furthermore, upon in vivo administration of rTNF-alpha these effectors, in addition to perforin and Fas ligand, are also armed with TNF-alpha cytotoxic molecules, thus resembling to the cytotoxic effectors from control mice. In a tumor model, immunized TNF-alpha-/- mice failed to reject the syngeneic fibrosarcoma MC57X, but did so when injected with rTNF-alpha. In vivo administration of anti-TNF-alpha mAb neutralized the effect of rTNF-alpha supporting the growth of MC57X cells. Our data provide novel evidence for TNF-alpha as an essential factor in (i) controlling cytotoxicity in vitro and in vivo and (ii) promoting tumor rejection in vivo.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Fibrosarcoma / immunology*
  • Killer Cells, Lymphokine-Activated / cytology
  • Killer Cells, Lymphokine-Activated / drug effects
  • Killer Cells, Lymphokine-Activated / immunology*
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Neoplasms, Experimental / immunology
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha