Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

Abstract

Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumorassociated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H-specific antibody in thioacetamide (TAA)-induced ICC in rats. Globo H-ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti-Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC. (Hepatology Communications 2021;0:1-15).

High expression of embryonic stem cell marker SSEA3 confers poor prognosis and promotes epithelial mesenchymal transition in hepatocellular carcinoma

“…This is consistent with our previous report that high expression of B3GALT5 and FUT1, key biosynthetic enzymes for SSEA3 and Globo H, is an independent predictor for the survival of HCC patients [ 12 ]. Similarly, Globo H expression is a poor prognostic indicator in intrahepatic cholangiocarcinoma [ 36 ]. In addition, we showed association of Globo H expression with vascular invasion in HCC.…”

“…Abnormal fucosylated GSLs including Globo H were identified by mass spectrometry in HCC in a previous study [ 43 ], consistent with our findings by immunohistochemistry. Indeed, we showed significant therapeutic efficacy of a Globo H antibody in rats with thioacetamide-induced cholangiocarcinoma [ 36 ]. Moreover, in a phase II clinical trial of Globo H-KLH vaccine in breast cancer, those patients who mounted Globo H-specific IgG and IgM antibodies had significantly better progression free survival [ 44 , 45 ].…”

Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review)

“…Previous findings have suggested that enhancing NK cell function or increasing the numbers of NK cells delays CCA progression, which may be a potential therapeutic target for CCA. Anti-Globo H antibody VK9 can enhance the activation and increase the presence of NK cells in the TIME, resulting in the inhibition of iCCA rat tumor growth ( 69 ). In vitro studies have demonstrated that the cytotoxic effect of activated NK cells on CCA cell lines may be augmented by cetuximab and cordycepin, effectively restraining CCA cell growth ( 70 , 71 ).…”

Tumor Microenvironment and its Implications for Antitumor Immunity in Cholangiocarcinoma: Future Perspectives for Novel Therapies

“…Existing research has suggested that CCA cells can induce the apoptosis of CD4 + , CD8 + T cells and CD56 + NK cells via the Fas/FasL pathway to produce immune evasion 75 . To study how to maintain or increase the antitumor activity of NK cells, Hung et al constructed a thioacetamide (TAA)-induced rat ICC model and suggested that the anti-Globo H antibody VK9 can facilitate the activation of NK cells in the tumor microenvironment, increase the Direct cytotoxicity and enhance ADCC function 76 . Panwong et al have suggested that cordycepin can increase the anti-CCA activity of NK-92, and TRAIL signaling may play a role in the immune regulation process of cordycepin 77 .…”