(1) In contrast to classical MHC class I molecules, MICA/B are expressed rarely on normal cells but frequently on tumor cells, including colon cancer, prostate cancer, HCC, and brain tumors.(2-5) The engagement of MICA/B and NKG2D strongly activates NK cells and costimulates T cells, enhancing their cytolytic ability and cytokine production. (6) Thus, the MICA/B-NKG2D pathway is an important mechanism by which the host immune system recognizes and kills transformed cells.(7) In addition to those membrane-bound forms, MICA/B are also cleaved proteolytically from tumor cells and appear as soluble forms in sera of patients with malignancy.(8-10) The levels of NKG2D expression tend to be decreased in patients with high levels of soluble MICA/B.(4) In addition, sera from those patients can downregulate NKG2D expression in vitro. (5,11) Hepatocellular carcinoma is one of the leading causes of cancer death worldwide. Chronic liver disease caused by hepatitis virus infection and non-alcoholic steatohepatitis leads to a predisposition for HCC; liver cirrhosis, in particular, is considered to be a premalignant condition. (14,15) 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 TAE is a wellestablished technique for unresectable HCC.(16) We reported previously that soluble MICA could be detected in sera of HCC patients.(17) However, the clinical significance of the soluble forms of NKG2D ligands in liver disease has not yet been established in a comprehensive manner, because the previous study was conducted on a small number of patients, did not include patients with premalignant conditions such as liver cirrhosis, and did not analyze its closely related molecule MICB. Furthermore, influences of therapeutic intervention on soluble NKG2D ligands in patients have been unclear. In the present study, we examined soluble MICA and soluble MICB in sera from a large number of patients with chronic liver diseases and HCC and their impact on NKG2D expression on immune cells during TAE therapy for HCC. 4 To whom correspondence should be addressed. E-mail: hayashin@gh.med.osaka-u.ac.jp 5 Keisuke Kohga and Tetsuo Takehara contributed equally to this work. Abbreviations: APC, allophycocyanin; ELISA, enzyme-linked immunosorbent assay; FITC, fluorescein isothiocyanate; HCC, hepatocellular carcinoma; MFI, mean fluorescence intensity; MICA/B, major histocompatibility complex (MHC) class I-related chain A and B; NK, natural killer; NKG2D, natural killer group 2, member D; PBMC, peripheral blood mononuclear cell; PE, phycoerythrin; TAE, transcatheter arterial embolization; TNM, tumor node metastasis.