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

Abstract

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 <i>ADAM9</i> mRNA levels in blood samples of advanced HCC patients (<i>n</i> = 10). In newly diagnosed patients (<i>n</i> = 5), the plasma <i>ADAM9</i> mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, <i>p</i> < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum <i>ADAM9</i> mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (<i>p</i> < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of <i>ADAM9</i> in tumor tissues was associated with poorer survival of HCC patients (log-rank <i>p</i> = 0.00039), while <i>ADAM10</i> and <i>ADAM17</i> exhibited no such association. In addition, <i>ADAM9</i> expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that <i>ADAM9</i> 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.