Hiramatsu Kosuke, Serada Satoshi, Kobiyama Kouji, Nakagawa Satoshi, Morimoto Akiko, Matsuzaki Shinya, Ueda Yutaka, Fujimoto Minoru, Yoshino Kiyoshi, Ishii Ken J, Enomoto Takayuki, Kimura Tadashi, Naka Tetsuji
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Japan.
Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
Cancer Sci. 2015 Oct;106(10):1474-8. doi: 10.1111/cas.12738.
Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) via effector cells such as tumor-infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti-bone marrow stromal antigen 2 (BST2) mAb against BST2-positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti-BST-2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti-BST2 mAb and CpG ODN monotherapy had a significant dose-dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti-BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P < 0.01), but not in NOG mice. FACS analysis revealed significantly increased numbers of NK cells and macrophages in tumors treated with a combination of anti-BST2 mAb and CpG ODN and with CpG ODN alone in SCID mice (P < 0.05 and P < 0.01, respectively). These results suggested that the combination therapy with anti-BST2 mAb and CpG ODN has a significant antitumor activity and induces tumor infiltration of NK cells and macrophages. Combination therapy with CpG ODN and anti-BST2 mAb or other antitumor mAb depending on ADCC may represent a new treatment option for cancer.
近年来，人们开发了许多靶向肿瘤抗原的单克隆抗体（mAb）。通过效应细胞（如肿瘤浸润性自然杀伤（NK）细胞和巨噬细胞）介导的抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞吞噬作用（ADCP），常常参与介导mAb的抗肿瘤活性。CpG寡脱氧核苷酸（ODN）具有强大的抗肿瘤活性，被认为可增加NK细胞和巨噬细胞向肿瘤的浸润。我们的研究小组之前报道，抗骨髓基质抗原2（BST2）单克隆抗体通过ADCC对BST2阳性子宫内膜癌细胞具有显著的抗肿瘤活性。在本研究中，我们使用SCID小鼠评估了抗BST-2单克隆抗体与CpG ODN联合治疗的协同抗肿瘤活性，并阐明了这种活性的潜在机制。抗BST2单克隆抗体和CpG ODN单一疗法均具有显著的剂量依赖性抗肿瘤活性（分别为P = 0.0135和P = 0.0196）。抗BST2单克隆抗体与CpG ODN联合治疗在SCID小鼠中具有显著的抗肿瘤活性（P < 0.01），但在NOG小鼠中则没有。流式细胞术分析显示，在SCID小鼠中，联合使用抗BST2单克隆抗体和CpG ODN以及单独使用CpG ODN治疗的肿瘤中，NK细胞和巨噬细胞的数量显著增加（分别为P < 0.05和P < 0.01）。这些结果表明，抗BST2单克隆抗体与CpG ODN联合治疗具有显著的抗肿瘤活性，并可诱导NK细胞和巨噬细胞向肿瘤浸润。将CpG ODN与抗BST2单克隆抗体或其他依赖ADCC的抗肿瘤单克隆抗体联合治疗，可能代表了一种新的癌症治疗选择。
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