Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors
Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors
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DOI：
10.1002/eji.200535549
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发表时间：
2006-04
影响因子：
5.4
通讯作者：
M. Nukiwa;S. Andarini;J. Zaini;H. Xin;M. Kanehira;Takuji Suzuki;T. Fukuhara;H. Mizuguchi;T. Hayakawa
中科院分区：
文献类型：
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作者：
M. Nukiwa;S. Andarini;J. Zaini;H. Xin;M. Kanehira;Takuji Suzuki;T. Fukuhara;H. Mizuguchi;T. Hayakawa
Fractalkine(CX3CL1)是一种独特的膜结合型趋化因子，对淋巴细胞具有很强的趋化作用。本研究的假设是，树突状细胞(DC)基因修饰的体外过表达Fractalkine可以增强T细胞介导的细胞免疫应答，从而诱导抗肿瘤免疫，从而抑制肿瘤生长。为了验证这一假说，不同的小鼠黑色素瘤细胞(B16-F10黑色素瘤，H-2b和结肠腺癌，H-2d)的已建立的肿瘤被瘤内注射经RGD纤维突变腺病毒载体(Ad-FKN)修饰的骨髓来源的DC。在所测试的两种肿瘤模型中，用Ad-FKN转导的DC治疗荷瘤小鼠，显著抑制了肿瘤的生长，并在治疗的小鼠中获得了生存优势。直接注射Ad-FKN转导的DC治疗肿瘤的免疫组织化学分析表明，治疗促进CD8+T细胞和CD4+T细胞在肿瘤环境中聚集，导致免疫相关过程的激活。与这一发现一致的是，瘤内给药Ad-FKN转导的DC可激发肿瘤特异性细胞毒性T淋巴细胞，这是在治疗宿主体内启动Th1免疫反应后产生的。此外，在CD4+T细胞缺陷小鼠和CD8+T细胞缺陷小鼠中，瘤内注射Ad-FKN转导的DC所提供的抗肿瘤作用也被完全消除。这些结果支持这样的概念，即用重组Fractalkine腺病毒载体对DC进行基因修饰可能是一种有用的癌症免疫治疗策略。
Fractalkine (CX3CL1) is a unique membrane‐bound CX3C chemokine that serves as a potent chemoattractant for lymphocytes. The hypothesis of this study is that dendritic cells (DC) genetically modified ex vivo to overexpress fractalkine would enhance the T cell‐mediated cellular immune response with a consequent induction of anti‐tumor immunity to suppress tumor growth. To prove this hypothesis, established tumors of different mouse cancer cells (B16‐F10 melanoma, H‐2b, and Colon‐26 colon adenocarcinoma, H‐2d) were treated with intratumoral injection of bone marrow‐derived DC that had been modified in vitro with an RGD fiber‐mutant adenovirus vector expressing mouse fractalkine (Ad‐FKN). In both tumor models tested, treatment of tumor‐bearing mice with Ad‐FKN‐transduced DC gave rise to a significant suppression of tumor growth along with survival advantages in the treated mice. Immunohistochemical analysis of tumors treated with direct injection of Ad‐FKN‐transduced DC demonstrated that the treatment prompted CD8+ T cells and CD4+ T cells to accumulate in the tumor milieu, leading to activation of immune‐relevant processes. Consistent with the finding, the intratumoral administration of Ad‐FKN‐transduced DC evoked tumor‐specific cytotoxic T lymphocytes, which ensued from in vivo priming of Th1 immune responses in the treated host. In addition, the anti‐tumor effect provided by intratumoral injection of Ad‐FKN‐transduced DC was completely abrogated in CD4+ T cell‐deficient mice as well as in CD8+ T cell‐deficient mice. These results support the concept that genetic modification of DC with a recombinant fractalkine adenovirus vector may be a useful strategy for cancer immunotherapy protocols.