Fig. 1.

Summary of important cells, ligands, cytokines and their receptors involved in the growth, development and death of HCC cells.

NK cells, as important components of our immune system, play a major role in different stages of HCC development. Their function is mainly regulated through interaction with other immune cells such as macrophages, dendritic cells and B-lymphocytes, which is mediated by different types of cytokines, ligands and their receptors. Macrophages and dendritic cells stimulate the NK cells by secretion pro-inflammatory cytokines such as IL-12 and IL-18. On the other hand, NK cells are also stimulated by the dendritic cells via their CD30 ligand. Interactions between B cells and NK cells occur via CD40 and CD40L leading to B cell maturation, isotype switching, antibody secretion, and NK cell-mediated IFN-ɤ production. Along with the abovementioned cytokines and ligands, IL-2, type I IFNs and TLR ligand cause further stimulation and increase in cytotoxicity of NK cells. Upon activation, NK cells secrete pro-inflammatory cytokines and use Fas/FasL and Granzyme/perforin- mediated mechanism to induce apoptosis of hepatic stellate cells and lysis of HBV/HCV-infected cells. NKG2A is an inhibitory receptor which suppresses NK cells through CD16 and CD56dim, thus leading to increased growth and development of HCC. NKG2D is another important receptor, which is activated upon binding to its ligand MICA/B on HCC cells, thus leading to increased cytotoxicity of NK cells and blockade of STAT3. All of these lead to the apoptosis of HCC cells and prevention of HCC progression and metastasis.