Cotransduction of CCL27 gene can improve the efficacy and safety of IL-12 gene therapy for cancer
Cotransduction of CCL27 gene can improve the efficacy and safety of IL-12 gene therapy for cancer
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DOI：
10.1038/sj.gt.3302892
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发表时间：
2007-01
期刊：
影响因子：
5.1
通讯作者：
Jian-Qing Gao;Jian-Qing Gao;N. Kanagawa;Yoshiaki Motomura;T. Yanagawa;T. Sugita;Yutaka Hatanaka;Yoichi Tani;H. Mizuguchi;Yasuo Tsutsumi;T. Mayumi;N. Okada;S. Nakagawa
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文献类型：
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作者：
Jian-Qing Gao;Jian-Qing Gao;N. Kanagawa;Yoshiaki Motomura;T. Yanagawa;T. Sugita;Yutaka Hatanaka;Yoichi Tani;H. Mizuguchi;Yasuo Tsutsumi;T. Mayumi;N. Okada;S. Nakagawa
白细胞介素-12（IL-12）是一种有效的抗肿瘤细胞因子，但高剂量是有毒的。在此，我们证明了IL-12和CC-趋化因子配体-27（CCL 27）基因联合转导到预先存在的小鼠OV-HM卵巢癌和Meth-A纤维肉瘤中，通过使用RGD纤维突变腺病毒载体，可以诱导肿瘤消退并比单独治疗更有效地减轻全身副作用。IL-12和CCL 27联合治疗的抗肿瘤活性是T细胞依赖性的，并且在再激发实验中证实了长期特异性免疫的发展。用CCL 27基因单独转导或用IL-12和CCL 27基因共转导的肿瘤的免疫组织化学分析显示浸润的CD 3 + T细胞的数量显著增加，所述浸润的CD 3 + T细胞包括CD 4+和CD 8+细胞。此外，IL-12和CCL 27基因共转导比单独转导CCL 27更有效地激活肿瘤浸润免疫细胞，如通过穿孔素阳性细胞的频率和IFN-γ的表达水平所确定的。此外，与单独用IL-12处理的小鼠相比，用IL-12和CCL 27组合处理的小鼠在肺、肝和脾中显示出较轻的病理变化，例如淋巴细胞浸润和髓外造血。我们的数据提供的证据表明，IL-12和CCL 27基因的组合体内转导是一种有前途的方法，用于开发癌症免疫基因治疗，可以同时招募和激活肿瘤浸润免疫细胞。
Interleukin-12 (IL-12) is a potent antitumoral cytokine, but high doses are toxic. Herein, we demonstrate that combinational transduction of IL-12 and CC-chemokine ligand-27 (CCL27) genes into pre-existing murine OV-HM ovarian carcinoma and Meth-A fibrosarcoma, by using RGD fiber-mutant adenoviral vectors, could induce tumor regression and relieve systemic side effects more effectively than either treatment alone. The antitumor activity of the IL-12 and CCL27 combination treatment was T-cell-dependent, and development of long-term specific immunity was confirmed in rechallenge experiments. Immunohistochemical analysis of tumors transduced with CCL27 gene alone or cotransduced with IL-12 and CCL27 genes showed significant increases in numbers of infiltrating CD3+ T cells, which included both CD4+ and CD8+ cells. Additionally, cotransduction with IL-12 and CCL27 genes could more efficiently activate tumor-infiltrating immune cells than transduction with CCL27 alone, as determined by the frequency of perforin-positive cells and expression levels of IFN-γ. Furthermore, mice treated with the IL-12 and CCL27 combination compared with those treated with IL-12 alone showed milder pathological changes, for example, lymphocyte infiltration and extramedullary hematopoiesis, in lung, liver and spleen. Our data provide evidence that combinational in vivo transduction with IL-12 and CCL27 genes is a promising approach for the development of cancer immunogene therapy that can simultaneously recruit and activate tumor-infiltrating immune cells.