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

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

Author information

1
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
2
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
3
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: lsu@med.unc.edu.
4
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address: sdwang@moon.ibp.ac.cn.

Abstract

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

PMID:
25016226
PMCID:
PMC4332697
DOI:
10.1016/j.jhep.2014.07.004
[Indexed for MEDLINE]
Free PMC Article

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