IFN-gamma-independent synergistic effects of IL-12 and IL-15 induce anti-tumor immune responses in syngeneic mice

Eur J Immunol. 2002 Jul;32(7):1914-23. doi: 10.1002/1521-4141(200207)32:7<1914::AID-IMMU1914>3.0.CO;2-P.


IL-15 and IL-12 display anti-tumor activity in different models and IFN-gamma has been reported as a secondary mediator of both IL-12 and IL-15 effects. TS/A murine adenocarcinoma cells were engineered to secrete IL-12, IL-15 or both cytokines. TS/A cells secreting IL-15 (TS/A-IL-15) displayed a reduced tumorigenicity (50%) when implanted subcutaneously in syngeneic mice, while both TS/A-IL-12 and TS/A-IL-12/IL-15 were rejected by 100% of animals. In contrast, TS/A-IL-15 and TS/A-IL-12 were tumorigenic in syngeneic IFN-gamma knockout mice (100% and >90% of take rate, respectively), but TS/A-IL-12/IL-15 were completely rejected by 90% of these mice. All IFN-gamma-deficient mice rejecting TS/A-IL-12/IL-15 developed protective immunity against wild-type TS/A, as indicated by re-challenge experiments. Immunohistochemical analysis of the TS/A-IL-12/IL-15 tumor rejection area in IFN-gamma-deficient mice showed a marked reactive cell infiltration constituted of CD8+ cells, granulocytes, NK cells, macrophages and dendritic cells associated with the expression of IL-1beta, TNF-alpha, GM-CSF, MCP-1 and MIP-2. In vivo depletion experiments showed that rejection of TS/A-IL-12/IL-15 cells required CD8+ T lymphocytes and also involved granulocytes, while CD4+ and NK cells played a minor role. These data show IFN-gamma-independent synergistic anti-tumor effects of IL-12 and IL-15, involving CD8+ cells and secondary chemokines and cytokines, such as TNF-alpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology*
  • Adenocarcinoma / pathology
  • Animals
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenicity Tests
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Granulocytes / immunology
  • Immunohistochemistry / methods
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology*
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology*
  • Killer Cells, Natural / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / immunology


  • Interleukin-15
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Interferon-gamma