Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy

Abstract

The mechanisms linking hepatitis B virus (HBV) and hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) remain largely unknown. Natural killer (NK) cells account for 25%-50% of the total number of liver lymphocytes, suggesting that NK cells play an important role in liver immunity. The number of NK cells in the blood and tumor tissues of HCC patients is positively correlated with their survival and prognosis. Furthermore, a group of NK cell-associated genes in HCC tissues is positively associated with the prolonged survival. These facts suggest that NK cells and HCC progression are strongly associated. In this review, we describe the abnormal NK cells and their functional impairment in patients with chronic HBV and HCV infection, which contribute to the progression of HCC. Then, we summarize the association of NK cells with HCC based on the abnormalities in the numbers and phenotypes of blood and liver NK cells in HCC patients. In particular, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may serve as a predictor for the occurrence of HCC. Finally, we present the current achievements in NK cell immunotherapy conducted in mouse models of liver cancer and in clinical trials, highlighting how chemoimmunotherapy, NK cell transfer, gene therapy, cytokine therapy and mAb therapy improve NK cell function in HCC treatment. It is conceivable that NK cell-based anti-HCC therapeutic strategies alone or in combination with other therapies will be great promise for HCC treatment.

Figure 1

Natural killer (NK) cell-based immunotherapy for hepatocellular carcinoma (HCC). NK cell-based immunotherapy to overcome the mechanism of NK cell dysfunction and to induce efficient NK cell immune responses is a promising therapeutic strategy. The strategy involves chemoimmunotherapy, adoptive transfer of NK cells or gene-modified NK cells, gene therapy and cytokine therapy, and therapy with a mAb specific for NK inhibitory receptors. Combined therapy that boosts NK cell activation and blocks inhibitory signaling pathways (eg, PD-1, CTLA-4, and KIR) has been shown to be more effective at reversing tumor-induced immune tolerance. A recent dual functional therapy strategy comprising both the stimulation of NK cell activation by inducing type I IFN production and the targeted inhibition of tumor growth-related genes has shown great promise for HCC therapy.