Hyper-IL-15 suppresses metastatic and autochthonous liver cancer by promoting tumour-specific CD8+ T cell responses

J Hepatol. 2014 Dec;61(6):1297-303. doi: 10.1016/j.jhep.2014.07.004. Epub 2014 Jul 10.


Background & aims: Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor α chain, on metastatic and autochthonous liver cancers.

Methods: Liver metastatic tumour models were established by intraportally injecting syngeneic mice with murine CT26 colon carcinoma cells or B16-OVA melanoma cells. Primary hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DEN). A hydrodynamics-based gene delivery method was used to achieve sustained hyper-IL-15 expression in the liver.

Results: Liver gene delivery of hyper-IL-15 robustly expanded CD8(+) T and NK cells, leading to a long-term (more than 40 days) accumulation of CD8(+) T cells in vivo, especially in the liver. Hyper-IL-15 treatment exerted remarkable therapeutic effects on well-established liver metastatic tumours and even on DEN-induced autochthonous HCC, and these effects were abolished by depletion of CD8(+) T cells but not NK cells. Hyper-IL-15 triggered IL-12 and interferon-γ production and reduced the expression of co-inhibitory molecules on dendritic cells in the liver. Adoptive transfer of T cell receptor (TCR) transgenic OT-1 cells showed that hyper-IL-15 preferentially expanded tumour-specific CD8(+) T cells and promoted their interferon-γ synthesis and cytotoxicity.

Conclusions: Liver delivery of hyper-IL-15 provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by preferentially expanding tumour-specific CD8(+) T cells and promoting their anti-tumour effects.

Keywords: Cytotoxicity; IFN-γ; Immunotherapy; Liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / pathology*
  • Cell Proliferation / drug effects*
  • Colonic Neoplasms / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Interleukin-15 / pharmacology
  • Interleukin-15 / therapeutic use*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / pathology
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / pathology
  • Recombinant Fusion Proteins / pharmacology
  • Recombinant Fusion Proteins / therapeutic use*
  • Treatment Outcome


  • IL-15Ralpha-sushi domain-linker-IL-15 fusion protein
  • Interleukin-15
  • Recombinant Fusion Proteins
  • Interleukin-12
  • Interferon-gamma