Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway

Eur J Immunol. 1998 Mar;28(3):1116-21. doi: 10.1002/(SICI)1521-4141(199803)28:03<1116::AID-IMMU1116>3.0.CO;2-A.


We have explored the role of an activation-induced T cell molecule, 4-1BB (CDw137), in the amplification of tumor immunity by retrovirus-mediated transduction of the 4-1BB ligand (4-1BBL) into tumor cells. Mice inoculated with P815 tumor cells expressing 4-1BBL developed a strong cytotoxic T lymphocyte (CTL) response and long-term immunity against wild-type tumor. The optimal effect of 4-1BBL in CTL stimulation required B7-CD28 interaction since blockade of this interaction by antibodies down-regulated the expression of 4-1BB on T cells and decreased CTL activity. Furthermore, co-expression of 4-1BBL and B7-1 in the poorly immunogenic AG104A sarcoma enhanced the induction of effector CTL and the rejection of the wild-type tumor while neither 4-1BBL nor B7-1 single transfectants were effective, suggesting a synergistic effect between the 4-1BB and the CD28 co-stimulatory pathways. Our results underscore the importance of the 4-1BB T cell stimulation pathway in the amplification of an antitumor immune response.

MeSH terms

  • Animals
  • Antigens, CD
  • Antigens, Neoplasm / immunology*
  • CD28 Antigens / administration & dosage*
  • CD4-Positive T-Lymphocytes / immunology
  • Cytotoxicity, Immunologic
  • Gene Transfer Techniques
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred DBA
  • Neoplasms, Experimental / immunology*
  • Receptors, Nerve Growth Factor / administration & dosage*
  • Receptors, Nerve Growth Factor / physiology*
  • Receptors, Tumor Necrosis Factor / administration & dosage*
  • Receptors, Tumor Necrosis Factor / physiology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9


  • Antigens, CD
  • Antigens, Neoplasm
  • CD28 Antigens
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9