Nukiwa Mio, Andarini Sita, Zaini Jamal, Xin Hong, Kanehira Masahiko, Suzuki Takuji, Fukuhara Tatsuro, Mizuguchi Hiroyuki, Hayakawa Takao, Saijo Yasuo, Nukiwa Toshihiro, Kikuchi Toshiaki
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Eur J Immunol. 2006 Apr;36(4):1019-27. doi: 10.1002/eji.200535549.
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.
趋化因子（CX3CL1）是一种独特的膜结合型CX3C趋化因子，可作为淋巴细胞的强效化学引诱剂。本研究的假设是，经体外基因改造以过表达趋化因子的树突状细胞（DC）将增强T细胞介导的细胞免疫反应，从而诱导抗肿瘤免疫以抑制肿瘤生长。为了验证这一假设，用表达小鼠趋化因子（Ad-FKN）的RGD纤维突变腺病毒载体在体外对骨髓来源的DC进行改造，然后将其瘤内注射到不同小鼠癌细胞（B16-F10黑色素瘤，H-2b，以及结肠26结肠腺癌，H-2d）形成的既定肿瘤中。在测试的两种肿瘤模型中，用Ad-FKN转导的DC治疗荷瘤小鼠可显著抑制肿瘤生长，并使治疗小鼠具有生存优势。对直接注射Ad-FKN转导的DC治疗的肿瘤进行免疫组织化学分析表明，该治疗促使CD8 + T细胞和CD4 + T细胞在肿瘤微环境中积聚，从而激活免疫相关过程。与该发现一致，瘤内注射Ad-FKN转导的DC可诱发肿瘤特异性细胞毒性T淋巴细胞，这是由治疗宿主中Th1免疫反应的体内启动引起的。此外，瘤内注射Ad-FKN转导的DC所提供的抗肿瘤作用在CD4 + T细胞缺陷小鼠以及CD8 + T细胞缺陷小鼠中完全消除。这些结果支持这样一种概念，即用重组趋化因子腺病毒载体对DC进行基因改造可能是癌症免疫治疗方案的一种有用策略。
