Natural killer cells in hepatocellular carcinoma: Anti-tumor effect and therapeutic potential

Natural killer (NK) cells are key players in the anti-tumor immune response in hematologic malignancy and solid tumors. NK-cells represent a relevant fraction of lymphocytes infiltrating the human liver and they are expected to control hepatocellular carcinoma (HCC) growth at least in the initial phases of tumorigenesis. This has been shown by preclinical data and clinical studies demonstrating association of NK-cell number, cytotoxic phenotype and function with outcome. For these reasons NK-cells represent anti-tumor immune cells with possible positive implications for immunotherapeutic approaches in patients with HCC. In order to understand functional properties and defects of this innate cell response in controlling HCC, several aspects have to be considered: the possible deregulation induced by chronic hepatitis B and C viral infections that represent the main causes of liver disease associated with HCC, the effect of tumor microenvironment by soluble mediators and the inhibitory effect of other immune elements involved in tumor-associated inflammatory response. High mortality of patients with primary liver tumors suggests tumor evasion mechanisms. Several mechanisms have been proposed to explain NK-cell dysfunction and different immunotherapeutic approaches can be envisaged to overcome HCC growth and spread. Autologous or allogeneic NK-cells have been adoptively transferred after in-vitro stimulation with promising clinical results. Soluble mediators and monoclonal antibodies activating NK-cell response are in the clinic for hematologic and solid malignancies and initial results are also available for HCC patients. Combined approaches based on increasing tumor sensitivity and potentiating NK-cell response are also under study.