Guo J, Wang B, Zhang M, Chen T, Yu Y, Regulier E, Homann H E, Qin Z, Ju D W, Cao X
Institute of Immunology, Second Military Medical University, Shanghai, PR China.
Gene Ther. 2002 Jun;9(12):793-803. doi: 10.1038/sj.gt.3301688.
Chemokine gene transfer represents a promising approach in the treatment of malignancies. Macrophage-derived chemokine (MDC) (CCL22) belongs to the CC chemokine family and is a strong chemoattractant for dendritic cells (DC), NK cells and T cells. Using adenoviral vectors, human MDC gene was transferred in vivo to investigate its efficacy to induce an antitumor response and to determine the immunologic mechanisms involved. We observed that intratumoral injection of recombinant adenovirus encoding human MDC (AdMDC) resulted in marked tumor regression in a murine model with pre-established subcutaneous 3LL lung carcinoma and induced significant CTL activity. The antitumor response was demonstrated to be CD4+ T cell- and CD8+ T cell-dependent. Administration of AdMDC induced chemoattraction of DC to the tumor site, facilitated DC migration to draining lymph nodes or spleen, and finally activated DC to produce high levels of IL-12. Furthermore, a significant increase of IL-4 production within the tumors was observed early after the AdMDC administration and was followed by the increase of IL-12 and IL-2 production. The levels of IL-2, IL-12 and IFN-gamma in serum, lymph nodes and spleen were also found to be higher in mice treated with AdMDC as compared with that in AdLacZ- or PBS-treated mice. The antitumor response induced by AdMDC was markedly impaired in IL-4 knockout mice, suggesting an important role of IL-4 in the induction of antitumor immunity by MDC. These results suggest that MDC gene transfer might elicit significant antitumor effects through efficient induction of antitumor immunity and might be of therapeutic potentials for cancer.
趋化因子基因转移是治疗恶性肿瘤的一种有前景的方法。巨噬细胞衍生趋化因子（MDC）（CCL22）属于CC趋化因子家族，是树突状细胞（DC）、自然杀伤细胞（NK细胞）和T细胞的强化学引诱剂。利用腺病毒载体，将人MDC基因进行体内转移，以研究其诱导抗肿瘤反应的功效，并确定其中涉及的免疫机制。我们观察到，在预先建立皮下3LL肺癌的小鼠模型中，瘤内注射编码人MDC的重组腺病毒（AdMDC）导致肿瘤显著消退，并诱导了显著的细胞毒性T淋巴细胞（CTL）活性。抗肿瘤反应被证明依赖于CD4 + T细胞和CD8 + T细胞。AdMDC的给药诱导DC向肿瘤部位趋化，促进DC迁移至引流淋巴结或脾脏，并最终激活DC产生高水平的白细胞介素-12（IL-12）。此外，在AdMDC给药后早期观察到肿瘤内白细胞介素-4（IL-4）产生显著增加，随后IL-12和白细胞介素-2（IL-2）产生增加。与用AdLacZ或磷酸盐缓冲盐水（PBS）处理的小鼠相比，用AdMDC处理的小鼠血清、淋巴结和脾脏中的IL-2、IL-12和干扰素-γ（IFN-γ）水平也更高。在IL-4基因敲除小鼠中，AdMDC诱导的抗肿瘤反应明显受损，表明IL-4在MDC诱导抗肿瘤免疫中起重要作用。这些结果表明，MDC基因转移可能通过有效诱导抗肿瘤免疫引发显著的抗肿瘤作用，并且可能具有癌症治疗潜力。
