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The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured  ADAM9  mRNA levels in blood samples of advanced HCC patients ( n  = 10). In newly diagnosed patients ( n  = 5), the plasma  ADAM9  mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00,  p  < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum  ADAM9  mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 ( p  < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of  ADAM9  in tumor tissues was associated with poorer survival of HCC patients (log-rank  p  = 0.00039), while  ADAM10  and  ADAM17  exhibited no such association. In addition,  ADAM9  expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that  ADAM9  mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.

cancers

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy