A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy
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Published on: September 12, 2019
Sooyeon Oh1, YoungJoon Park2, Hyun-Jung Lee3
1Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea.
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 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.
Insights
ADAM9 mRNA levels are elevated in hepatocellular carcinoma (HCC) patients and may predict response to immunotherapy. Targeting the ADAM9-MICA-NKG2D pathway could improve HCC treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) progression involves mechanisms that allow tumor cells to evade immune surveillance.
- Malignant cells can shed Major Histocompatibility Complex (MHC) class I-related chain A (MICA) from their surface, a ligand for Natural Killer (NK) group 2 member D (NKG2D) receptors, thereby impairing anti-tumor immune responses.
- A disintegrin and metalloprotease 9 (ADAM9) has been identified as a key enzyme involved in MICA shedding.
Purpose of the Study:
- To investigate the role of ADAM9 in hepatocellular carcinoma (HCC).
- To assess ADAM9 mRNA levels as a potential biomarker for predicting clinical response to immunotherapy in HCC patients.
- To explore the therapeutic potential of targeting the ADAM9-MICA-NKG2D axis in HCC.
Main Methods:
- Measurement of ADAM9 mRNA levels in plasma samples from advanced HCC patients and healthy controls.
- Analysis of ADAM9 mRNA levels in HCC patients before and after nivolumab therapy.
- Correlation analysis of ADAM9 expression with patient survival and immune checkpoint molecules using The Cancer Genome Atlas (TCGA) database.
Main Results:
- Plasma ADAM9 mRNA levels were significantly higher in newly diagnosed HCC patients compared to healthy controls.
- In HCC patients treated with nivolumab, a clinical response was associated with a significant decrease in serum ADAM9 mRNA levels.
- Higher ADAM9 expression in tumor tissues correlated with poorer survival in HCC patients and was positively associated with inhibitory checkpoint molecule expression.
Conclusions:
- ADAM9 mRNA may serve as a predictive biomarker for immunotherapy response in HCC.
- The ADAM9-MICA-NKG2D pathway represents a promising therapeutic target for enhancing HCC immunotherapy.
- Further research is needed to validate these findings in larger cohorts.
