肿瘤细胞治疗研究
英文原题：Trastuzumab-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Enhances Natural Killer Cell Cytotoxicity in HER2-Overexpressing Ovarian Cancer.
尽管人表皮生长因子受体 2（HER2）过表达是卵巢癌的一种不良预后分子标志物，在近 30% 的卵巢癌病例中存在，但针对 HER2 过表达卵巢癌尚无成熟疗法。
卵巢癌是死亡率最高的妇科恶性肿瘤。人表皮生长因子受体2（HER2）过表达是卵巢癌的不良预后分子标志物，约30%的卵巢癌病例可见此现象，但目前尚无已确立的HER2过表达卵巢癌疗法。本研究在HER2过表达卵巢癌临床前模型中，考察曲妥珠单抗生物类似药赛妥珠单抗（samfenet）联合自然杀伤（NK）细胞的疗效。首先，我们检测了3种卵巢癌细胞系和8份卵巢癌患者来源肿瘤异种移植（PDTX）样本中的HER2表达，并依据临床标准开展免疫组织化学和银原位杂交（SISH）。与HER2低表达细胞相比，HER2过表达细胞对samfenet最为敏感。此外，samfenet联合NK细胞显著提高了对HER2过表达细胞的杀伤敏感性；与单药治疗相比，该联合方案在PDTX小鼠中显示显著抗肿瘤作用。已知曲妥珠单抗等抗HER2人源化IgG1单克隆抗体可诱导抗体依赖性细胞毒作用（ADCC）。与此相符，体外NK细胞毒性实验和体内抗肿瘤疗效均证实，samfenet联合NK细胞可产生NK细胞介导的ADCC。异种移植瘤的末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）实验也支持这一ADCC作用，联合组凋亡细胞数量增加。此外，基于公开mRNA表达数据，HER2高表达与较短的无进展生存期和总生存期相关。本研究表明，samfenet联合NK细胞疗法可能通过ADCC成为HER2过表达卵巢癌患者一种有前景的治疗策略。因此，本研究支持进一步开展该联合疗法治疗HER2过表达卵巢癌患者的临床研究。
Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer.
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