NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.Cellular & Molecular Immunology advance online publication, 6 October 2014; doi:10.1038/cmi.2014.91.

Figure 1

The imbalance of NK cell receptors and dysfunction of NK cells in the HCC microenvironment. The phenotype and function of NK cells are influenced by the surrounding liver and tumor microenvironment. The imbalance of NK cell receptors is characterized by downregulated activating receptors and increased expression of inhibitory receptors, which contribute to the dysfunction of NK cells and progression of HCC. For example, TGF-β secreted by Treg or HCC cells downregulates the surface expression of NKG2D or other activating NK cell receptors. PGE2 and IDO derived from tumor cells or activated TAFs can also downregulate NKG2D expression. sMICA or sULBP shed from tumor cells is associated with downregulated NKG2D expression and impairs the activation of NK cells. The suppressive cells—MDSCs, monocytes/macrophages from intratumoral tissues and M2-polarized TAMs—also suppress the expression of NK cell-activating receptors and impair NK cell function by secreting TGF-β and IL-10 or IDO. In addition, persistent HBV infection, the main risk factor for HCC, increases the expression of inhibitory receptors (e.g., NKG2A and Tim-3) and reduces the expression of activating receptors on NK cells. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MDSC, myeloid-derived suppressor cell; NK, natural killer; TAF, tumor-associated fibroblast; TAM, tumor-associated macrophage; TGF, transforming growth factor; Treg, regulatory T.