Restoration of natural killer activity in hepatocellular carcinoma by treatment with antibody against granulin-epithelin precursor

Abstract

Impairment of natural killer (NK) cell activity is an important mechanism of tumor immunoevasion. We have previously shown that expression of granulin-epithelin precursor (GEP) in hepatocellular carcinoma (HCC) cells rendered the cells resistant to NK cell immunosurveillance. Here, we examined whether targeting GEP could rescue NK activity in HCC patients. The current study demonstrated that quantities and activities of NK cells were significantly lower in HCC patients compared with healthy individuals, and were negatively correlated with GEP levels in HCC cells. NK cells demonstrated enhanced expression of the stimulatory receptors natural-killer group 2, member D (NKG2D) and CD69, increased secretion of IFN-γ and perforin, and cytotoxicity against HCC cells upon GEP suppression. Opposite phenotypes of NK cells were observed when GEP was overexpressed in HCC cells. Importantly, GEP blockage by monoclonal antibody A23 restored NK activity in HCC patients and sensitized HCC cells to NK cytotoxicity. Furthermore, A23 induced NK-mediated antibody-dependent cell-mediated cytotoxicity against HCC. In summary, the activity of NK cells in HCC was impaired by GEP expression, which could be rescued by GEP antibody. This study provides new insight for treatments targeting GEP to boost NK activity in HCC patients.

Keywords:

• cytotoxicity
• interferon-gamma
• MHC class I chain-related molecule A
• natural-killer group 2
• member D
• perforin

Abbreviations:

• ADCC, antibody-dependent cell-mediated cytotoxicity
• CSC, cancer stem cell
• GEP, granulin-epithelin precursor
• HCC, hepatocellular carcinoma
• IFN, interferon
• MICA, MHC class I chain-related gene A
• NK, natural killer
• ULBP, unique long 16-binding protein

Disclosure of Potential Conflicts of Interest

The University of Hong Kong has filed patent applications for the described works. STC has received Pfizer collaborative research grants. Providers of funding had no role in study design, data collection, analysis, interpretation of the data, writing of the article, or the decision to submit the article for publication. The other authors declare no conflict of interest.

Funding

This study was supported in part by Hong Kong Research Grants Council (GRF 764111, 764112), Health and Medical Research Fund (01121536 and 01121566) and Sun C.Y. Research Foundation for Hepatobiliary and Pancreatic Surgery of the University of Hong Kong.