Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
Hepatobiliary Pancreat Dis Int. 2022 Oct;21(5):485-492. doi: 10.1016/j.hbpd.2022.03.006. Epub 2022 Mar 10.
Cholangiocarcinoma (CCA) is one of the primary hepatobiliary malignant neoplasms with only 10% of 5-year survival rate. Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA. The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis. This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1 (PD-1) in CCA mouse model.
We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro, including both intrahepatic CCA and extrahepatic CCA cells. We examined the in vitro effect of verteporfin on cell proliferation, apoptosis, and stemness. We evaluated the in vivo efficacy of verteporfin, anti-PD-1, and a combination of both in subcutaneous CCA mouse model.
Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion. Nevertheless, verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation, decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers (all P < 0.05). The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.
Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.
胆管癌（CCA）是原发性肝胆恶性肿瘤之一，5 年生存率仅为 10%。免疫检查点阻断的有前途的免疫疗法在 CCA 中没有明显获益。维替泊芬抑制 YAP1 信号已显示出通过抑制细胞增殖和诱导细胞凋亡的可喜结果。本研究旨在评估维替泊芬与抗程序性细胞死亡 1（PD-1）联合应用于 CCA 小鼠模型的潜在益处。
我们评估了维替泊芬在体外人 CCA 细胞系中的细胞毒性，包括肝内 CCA 和肝外 CCA 细胞。我们研究了维替泊芬对细胞增殖、凋亡和干性的体外作用。我们评估了维替泊芬、抗 PD-1 以及两者联合应用于皮下 CCA 小鼠模型的体内疗效。
我们的研究表明，维替泊芬以剂量依赖性方式减少了体外人 CCA 肿瘤细胞的生长并增强了其凋亡。然而，维替泊芬损害了干性，表现为球体形成和集落形成减少，具有醛脱氢酶活性和阳性癌症干细胞标志物的细胞数量减少（均 P<0.05）。维替泊芬与抗 PD-1 的联合应用与单独使用任一药物相比，减少了 CCA 皮下 SB1 肿瘤模型中的肿瘤负担。
维替泊芬在肝内和肝外 CCA 细胞系中均表现出抗肿瘤作用，与抗 PD-1 的联合应用抑制了肿瘤生长。
