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 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.

The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients

“…This included 11 clinical trials (4 randomized and 7 nonrandomized) and 8 cohort studies (Table 1), 12 case series, and 32 case reports (supplemental online Table 3). Fifty of the articles described the use of immunotherapy agents in the setting of unresectable HCC [13, 14, 18, 29–75], 3 in the neoadjuvant setting [76–78], and 10 in the setting of LT [79–88], and they reported on 2,402 patients in total (Fig. 1).…”

“…The mean score of the NOS scale for the nonrandomized studies [13, 14, 30, 35, 36, 42, 45, 53, 56–58, 60, 66, 70, 73] was 7.4 ± 0.6 (supplemental online Table 5). The mean score of the NHBLI scale for the case series [31, 32, 37, 39, 40, 44, 51, 62, 67, 77, 80, 84] was 6.8 ± 0.9 (supplemental online Table 6). The mean score of the JBI scale for the case reports [29, 33, 34, 38, 41, 43, 46–50, 52, 55, 61, 64, 65, 68, 69, 71, 72, 74–76, 78, 79, 81–83, 85–88] was 7.2 ± 1.1 (supplemental online Table 7).…”

Interleukin-2 inducible T-cell kinase: a potential prognostic biomarker and tumor microenvironment remodeling indicator for hepatocellular carcinoma

“…Immunotherapy has been considered a novel treatment with great potential for patients with HCC. Nivolumab (Opdivo) has been approved for second-line treatment in HCC [ 24 ]. Obstructions in detecting and analyzing the comprehensive immune microenvironment of each patient in a clinical context mean that there are still obstacles in therapeutic target identification and efficacy monitoring of immunotherapy for HCC.…”

ADAM and ADAMTS Proteins, New Players in the Regulation of Hepatocellular Carcinoma Microenvironment

“…Comparison of adamalysin expression levels between tumor (T) and adjacent non-tumor (NT) tissues and survival analyses are given in Table 1 , left and right panels, respectively. Note that the same TCGA-LIHC samples were recently used to propose ADAM9 as a biomarker in advanced HCC [ 57 ]. In agreement with previous reports, we observed that expression levels of ADAM9, ADAM10, ADAM12 and ADAM17 were increased in tumor versus adjacent non tumor tissues except for ADAM10 that was non-significant, all were associated with poor prognosis.…”