IL15 combined with Caspy2 provides enhanced therapeutic efficiency against murine malignant neoplasm growth and metastasis
IL15 combined with Caspy2 provides enhanced therapeutic efficiency against murine malignant neoplasm growth and metastasis
复制标题
DOI：
10.1038/cgt.2012.17
复制
发表时间：
2012-04
影响因子：
6.4
通讯作者：
Yu Yang;Xin Zhang;Na Zhang;Lin Cheng;Can Li;Sizhong Zhang;Junfeng Zhang;Lei Dai;H. Tian;N. Yan;Ping Fan;L. Dai;Fen Xu;G. Shi;Xiaolei Chen;Tao Du;Y. Li;Yuquan Wei;Hongxin Deng
中科院分区：
文献类型：
--
作者：
Yu Yang;Xin Zhang;Na Zhang;Lin Cheng;Can Li;Sizhong Zhang;Junfeng Zhang;Lei Dai;H. Tian;N. Yan;Ping Fan;L. Dai;Fen Xu;G. Shi;Xiaolei Chen;Tao Du;Y. Li;Yuquan Wei;Hongxin Deng
白细胞介素-15（IL-15）是一种潜在的肿瘤免疫治疗药物。Caspy 2是一种具有活性的斑马半胱天冬酶，在小鼠肿瘤中诱导细胞凋亡和免疫应答。在这项研究中，我们的目的是评估使用IL 15和Caspy 2对小鼠肿瘤的基因治疗的潜力。构建表达Caspy 2和IL 15基因的质粒，用DOTAP/胆固醇阳离子脂质体包封，瘤内注射给CT 26、B16-F10和4 T1荷瘤小鼠。我们发现IL 15和Caspy 2的共表达可以显著抑制肿瘤的生长，并延长CT 26或B16 F10荷瘤小鼠的生存期。在4 T1肿瘤模型中观察到自发性肺转移的显著减少。在CT 26模型中，IL 15和Caspy 2处理的小鼠获得了对亲代肿瘤细胞再攻击的长期保护性免疫。细胞毒性T淋巴细胞和末端脱氧核苷酸转移酶介导的缺口末端标记实验表明，capsy 2和IL 15的组合可以增强细胞凋亡和免疫应答诱导，这可能是其非凡的抗肿瘤作用的原因。此外，我们发现，观察到的IL 15和Caspy 2的肿瘤抑制与Caspy 2介导的IL 10下调和干扰素-γ和肿瘤坏死因子-α上调一致。因此，我们的研究结果表明，联合方案可能是一种新的和有效的癌症治疗策略。
Interleukin-15 (IL15) is a potential immunotherapeutic treatment for cancer. Caspy2 is an active zebra caspase for inducing apoptosis and immune response in murine tumors. In this study, we aim to evaluate the potential of gene therapy using IL15 and Caspy2 against the murine tumors. Plasmid expressing both Caspy2 and IL15 genes was constructed, encapsulated in DOTAP/cholesterol cationic liposome and injected intratumorally into the mice bearing CT26, B16-F10 and 4T1 carcinoma. We found that coexpression of IL15 and Caspy2 could significant inhibit tumor growth and prolong survival of the mice bearing CT26 or B16F10 tumor. A significant reduction in spontaneous lung metastasis was observed in the 4T1 tumor model. In CT26 model, the mice treated with IL15 and Caspy2 acquired a long-time protective immunity against the parental tumor cell rechallenge. Cytotoxic T lymphocytes and terminal deoxynucleotidyltransferase-mediated nick end labelling assays showed that the combination of capsy2 and IL15 could enhance both the apoptosis and immune response induction, which may account for its extraordinary antitumor effect. Furthermore, we showed that the observed tumor suppression by IL15 and Caspy2 concurred with the Caspy2-mediated downregulation of IL10 and upregulation of interferon-γ and tumor necrosis factor-α. Our results therefore suggested that the combination regimen might be a novel and effective strategy for cancer treatment.