NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation

Dongping Xu, Peidi Gu, Ping Ying Pan, Qingsheng Li, Alice I. Sato, Shu Hsia Chen

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


In previous reports, systemic administration of a stimulatory monoclonal antibody directed against the 4-1BB receptor had no effect on survival or tumor burden in mice inoculated with the poorly immunogenic B16-F10 melanoma. We combined IL-12 gene transfer with 4-1BB costimulation to explore a previously noted cooperative anti-tumor effect against this model tumor. We hypothesize that the innate immune response mediated by IL-12-activated natural killer (NK) cells initiates the activation of the immune system, leading to the priming of T cells, whereas 4-1BB costimulation enhances the function of primed tumor-specific T cells. The effect of the combination therapy on the growth of subcutaneous (s.c.) tumors and pulmonary metastasis was examined. The combination therapy significantly retarded the growth of subcutaneously-inoculated tumors, and 50% of tumor-bearing mice survived with complete tumor regression. In contrast, neither IL-12 gene transfer nor anti-4-1BB antibody administration alone was as effective. Enhanced CTL activity against both B16-F10 tumor cells and TRP-2-pulsed EL4 syngeneic tumor cells was observed in tumor-bearing animals treated with the combination therapy 2 weeks after treatment and, in long-term survivors from this combination therapy, at > 120 days. In a pulmonary metastatic model, only the combination therapy generated significant protection against metastasis. In vivo depletion of NK or CD8+ but not CD4+ subsets eliminated the protective immunity. Furthermore, NK cell depletion significantly reduced both tumor-specific CTL activity and the number of tumor-specific IFN-γ-producing cells, suggesting that this synergistic effect requires the participation of both NK and CD8+ T cells.

Original languageEnglish (US)
Pages (from-to)499-506
Number of pages8
JournalInternational Journal of Cancer
Issue number4
StatePublished - Apr 20 2004


  • 4-1BB (CD137)
  • Gene therapy
  • Immune modulation
  • Interleukin-12
  • Melanoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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