The results suggested that MICA might be cleaved at the intracellular ADAM9-recognized cleavage site and was further cleaved at the extracellular ADAM9-independent cleavage site in HCC cells, resulting in the production of soluble MICA. Immunohistochemical analysis revealed that ADAM9 was overexpressed in human HCC compared to normal

liver tissues. The cytolytic activity of natural killer (NK) cells against ADAM9KD-HCC cells was higher than that against control cells, and the enhancement of this cytotoxicity depended on the MICA/B and NK group 2, member D pathway. Sorafenib treatment resulted in decreased expression of ADAM9, Tamoxifen increased expression of membrane-bound MICA expression, and decreased levels of soluble MICA in HCC cells. Adding sorafenib enhanced the NK sensitivity of HCC cells via increased expression of membrane-bound MICA. Conclusion: ADAM9 is involved

in MICA ectodomain shedding in HCC cells, and sorafenib can modulate ADAM9 expression. Sorafenib therapy may have a previously unrecognized effect on antitumor immunity in patients with HCC. (HEPATOLOGY 2010.) Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Chronic liver disease caused by hepatitis virus infection and nonalcoholic steatohepatitis leads to a predisposition for HCC; liver cirrhosis, in particular, is considered to be a premalignant condition.1, 2 With regard to treatment, surgical resection or percutaneous techniques such as ethanol injection and radiofrequency ablation are considered to be choices for curable treatment of localized HCC, whereas transarterial chemoembolization Akt inhibitor (TACE) is a well-established technique for more advanced HCC.3 The liver contains both a large compartment

of innate immune cells (natural killer [NK] cells and NK T cells) and acquired immune cells (T cells),4, 5 but the activation of these immune cells after HCC treatment remains unclear. If such treatments can efficiently activate abundant immune cells in the liver, this could lead to the establishment of attractive new strategies for HCC treatment. Major histocompatibility complex (MHC) class I–related chain A (MICA) is a ligand for NK group 2, member D (NKG2D) receptors expressed on a variety of immune cells.6 In contrast to classical MHC class I molecules, MICA is rarely expressed on normal cells but frequently Verteporfin on tumor cells.7–10 The engagement of MICA and NKG2D strongly activates NK cells, enhancing their cytolytic activity and cytokine production.11 Thus, the MICA-NKG2D pathway is an important mechanism by which the host immune system recognizes and kills transformed cells.12 In addition to those membrane-bound forms, MICA molecules are cleaved proteolytically from tumor cells and appear as soluble forms in sera of patients with malignancy, including HCC.13–17 The release of soluble MICA/MHC class I–related chain B (MICB) from tumor cells is thought to antagonize NKG2D-mediated immunosurveillance.