Trastuzumab-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Enhances Natural Killer Cell Cytotoxicity in HER2-Overexpressing Ovarian Cancer

被引:0
作者
Hong, Sa Deok [1 ]
Katuwal, Nar Bahadur [1 ]
Kang, Min Sil [1 ]
Ghosh, Mithun [1 ]
Park, Seong Min [1 ]
Kim, Tae Hoen [2 ]
Baek, Young Seok [1 ,3 ]
Lee, Seung Ryeol [4 ]
Moon, Yong Wha [5 ]
机构
[1] CHA Univ, Grad Sch, Dept Biomed Sci, Seongnam 13488, South Korea
[2] CHA Univ, CHA Bundang Med Ctr, Dept Pathol, Seongnam 13496, South Korea
[3] CHA Biotech, R&D Div, Immunotherapy Team, New Biol Ent NBE Res, Seongnam Si 13488, South Korea
[4] CHA Univ, CHA Bundang Med Ctr, Dept Urol, Seongnam Si 13496, South Korea
[5] CHA Univ, CHA Bundang Med Ctr, Dept Internal Med, Div Hematol Oncol, Seongnam Si 13496, South Korea
基金
新加坡国家研究基金会;
关键词
HER2-overexpressed ovarian cancer; trastuzumab; NK cell; ADCC; BREAST-CANCER; FC-RECEPTORS; THERAPY; MECHANISMS; RESISTANCE; HER2;
D O I
10.3390/ijms252111733
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页数:17
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