胆管癌（CCA）是一种侵袭性且致命的癌症。预后很差，目前还没有制定最佳的化疗方案。人表皮生长因子受体 2（HER2、neu 和 erbB2）在乳腺癌中高表达，并在许多其他肿瘤中表达，但在 CCA 中表达较差。抗 HER2 抗体曲妥珠单抗已用于治疗 HER2 阳性乳腺癌和胃癌。在本研究中，我们通过流式细胞术检测了 7 个泰国肝吸虫相关 CCA 细胞系的 HER2 表面表达，发现所有这些 CCA 细胞均呈 HER2 弱阳性。 MTT分析显示曲妥珠单抗直接抑制CCA的生长。通过使用在 NFAT 反应元件控制下的携带 FcR 的重组 Jurkat T 细胞表达萤火虫荧光素酶基因，我们定义了抗体依赖性细胞毒性 (ADCC) 和抗体依赖性细胞吞噬作用 (ADCP) 的活性。 ADCC 通过使用扩增的 NK 细胞得到证实。 ADCP通过使用小鼠腹腔巨噬细胞和人单核细胞来源的巨噬细胞作为效应细胞得到证实。给予兔血清以测试曲妥珠单抗的补体依赖性细胞毒性（CDC）活性。最后，我们评估了曲妥珠单抗在体内患者来源的细胞异种移植和患者来源的异种移植（PDX）模型中的疗效。我们的结果表明，一个独特的 CCA（肝吸虫相关 CCA）群体表达 HER2。曲妥珠单抗在体外和体内通过多种机制表现出对 HER2 弱阳性 CCA 的有效抑制作用。因此，HER2 是抗 CCA 治疗中一个有前途的靶点，而曲妥珠单抗可以被认为是治疗 CCA 的有前途的抗体免疫治疗剂。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Cholangiocarcinoma (CCA) is an aggressive and fatal cancer. The prognosis is very poor and no optimal chemotherapy has been established. Human epidermal growth factor receptor 2 (HER2, neu, and erbB2) is highly-expressed in breast cancer and is expressed in many other tumors but poorly expressed in CCA. The anti-HER2 antibody, trastuzumab, has been used for the treatment of HER2-positive breast and gastric cancer. In this study, we examined the surface expression of HER2 on seven Thai liver-fluke-associated CCA cell lines by flow cytometry, and found all of these CCA cells were weakly positive for HER2. MTT assay revealed that trastuzumab directly suppressed the growth of CCA. By using FcR-bearing recombinant Jurkat T-cell-expressing firefly luciferase gene under the control of NFAT response elements, we defined the activities of antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP). ADCC was confirmed by using expanded NK cells. ADCP was confirmed by using mouse peritoneal macrophages and human monocyte-derived macrophages as effector cells. Rabbit serum was administered to test the complement-dependent cytotoxicity (CDC) activity of trastuzumab. Finally, we evaluated the efficacy of trastuzumab in in vivo patient-derived cell xenograft and patient-derived xenograft (PDX) models. Our results showed that a distinct population of CCA (liver-fluke-associated CCA) expressed HER2. Trastuzumab demonstrated a potent inhibitory effect on even HER2 weakly positive CCA both in vitro and in vivo via multiple mechanisms. Thus, HER2 is a promising target in anti-CCA therapy, and trastuzumab can be considered a promising antibody immunotherapy agent for the treatment of CCA.Copyright © 2024 Elsevier B.V. All rights reserved.