Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells.

Shin Hwang,Dong-Hwan Jung,Gil-Chun Park,Ji-Seok Baek,Chul-Soo Ahn,Sung-Gyu Lee,Jaeseok Han,Gi-Won Song,Eunyoung Tak,Nayoung Kim

doi:10.3390/ijms20071564

Abstract

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients.

Highlights

The two key functions of natural killer (NK) cells are cytotoxicity against tumor and virus-infected cells and the production of cytokines and chemokines, such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)
The cytotoxicity of NK cells is achieved by lytic molecules, such as perforin and granzyme B [1,2], or by inducing apoptosis through death receptors on the surfaces of target cells
The results of this study showed that Hepatic intrasinusoidal (HI) NK cells, in particular the CD56bright subset, had strong cytotoxicity against certain hepatocellular carcinoma (HCC) cell lines which expressed NKG2D ligands and FAS, supporting potential cancer immunotherapy using HI NK cells

Summary

Introduction

The two key functions of natural killer (NK) cells are cytotoxicity against tumor and virus-infected cells and the production of cytokines and chemokines, such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). The cytotoxicity of NK cells is achieved by lytic molecules, such as perforin and granzyme B [1,2], or by inducing apoptosis through death receptors on the surfaces of target cells. The effector function of NK cells is mediated by multiple activating and inhibitory receptors. A majority of Ly49 molecules in mice and killer-cell immunoglobulin-like receptors (KIRs) in humans are typical inhibitory receptors on the surface of NK cells [5]. Subsets of NK cells express programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) [6,7], which have been intensively investigated as immune checkpoint receptors for the development of novel cancer therapeutics. NK cells express other inhibitory receptors such as CD94/NKG2A, immunoglobulin-like transcript 2 (ILT2; CD85j), and B- and T-lymphocyte attenuator (BTLA) [8]

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Results