title: 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.
authors.affiliation: Department of Surgery ; Center for Cancer Research; The University of Hong Kong ; Hong Kong, China.
authors.forename: Phyllis Fy
authors.initials: PF
authors.lastname: Cheung
authors.affiliation: Department of Surgery ; Center for Cancer Research; The University of Hong Kong ; Hong Kong, China.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Yip
authors.affiliation: Department of Surgery.
authors.forename: Linda Wc
authors.initials: LW
authors.lastname: Ng
authors.affiliation: Department of Chemical Pathology; The Chinese University of Hong Kong; Prince of Wales Hospital ; Hong Kong, China.
authors.forename: Chun Kwok
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Department of Surgery ; Department of Surgery; Queen Mary Hospital ; Hong Kong, China.
authors.forename: Tan To
authors.initials: TT
authors.lastname: Cheung
authors.affiliation: Department of Surgery ; Department of Surgery; Queen Mary Hospital ; Hong Kong, China.
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Surgery ; Department of Surgery; Queen Mary Hospital ; Hong Kong, China.
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.affiliation: Department of Surgery ; Center for Cancer Research; The University of Hong Kong ; Hong Kong, China.
authors.forename: Siu Tim
authors.initials: ST
authors.lastname: Cheung
keywords: ADCC, antibody-dependent cell-mediated cytotoxicity; CSC, cancer stem cell; GEP, granulin-epithelin precursor; HCC, hepatocellular carcinoma; IFN, interferon; MHC class I chain-related molecule A; MICA, MHC class I chain-related gene A; NK, natural killer; ULBP, unique long 16-binding protein; cytotoxicity; interferon-gamma; member D; natural-killer group 2; perforin