Prolonged, NK Cell-Mediated Antitumor Effects of Suicide Gene Therapy Combined with Monocyte Chemoattractant Protein-1 against Hepatocellular Carcinoma
Prolonged, NK Cell-Mediated Antitumor Effects of Suicide Gene Therapy Combined with Monocyte Chemoattractant Protein-1 against Hepatocellular Carcinoma
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DOI：
10.4049/jimmunol.178.1.574
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发表时间：
2006-03
期刊：
影响因子：
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通讯作者：
T. Tsuchiyama;Y. Nakamoto;Y. Sakai;Y. Marukawa;M. Kitahara;N. Mukaida;S. Kaneko
中科院分区：
文献类型：
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作者：
T. Tsuchiyama;Y. Nakamoto;Y. Sakai;Y. Marukawa;M. Kitahara;N. Mukaida;S. Kaneko
肝细胞癌（HCC）根治性治疗后肿瘤复发率仍然很高。免疫调节剂，包括趋化因子，被认为可以增强自杀基因治疗诱导的肿瘤细胞凋亡的抗肿瘤作用。因此，我们评估了表达HSV胸苷激酶和MCP-1的双顺反子重组腺病毒载体（rAd）对肝癌细胞的免疫调节作用。使用无胸腺裸鼠模型（BALB/c-nu/nu），将原代s.c.用rAd完全根除肿瘤（HuH 7;人HCC细胞），然后用更昔洛韦处理。随后用HCC细胞再次激发相同的动物，监测肿瘤发展，并通过化学方法或通过测量IFN-γ mRNA表达来分析NK细胞的募集或活化。与仅用表达HSV胸苷激酶基因的rAd治疗的小鼠相比，肿瘤生长被显著抑制（p < 0.001）。肿瘤生长的抑制与血清IL-12和IL-18的升高相关。在抑制过程中，NK细胞被专门招募，肿瘤组织中Th 1细胞因子基因表达增强。然而，当用抗去唾液酸GM 1 Ab灭活NK细胞或当施用抗IL-12和抗IL-18 Ab时，抗肿瘤活性被消除。这些结果表明，自杀基因治疗，连同MCP-1的交付，根除HCC细胞，并发挥长期的NK细胞介导的抗肿瘤作用，在HCC模型中，这表明一个合理的策略，以防止肿瘤复发。
Tumor recurrence rates remain high after curative treatments for hepatocellular carcinoma (HCC). Immunomodulatory agents, including chemokines, are believed to enhance the antitumor effects of tumor cell apoptosis induced by suicide gene therapy. We therefore evaluated the immunomodulatory effects of a bicistronic recombinant adenovirus vector (rAd) expressing both HSV thymidine kinase and MCP-1 on HCC cells. Using an athymic nude mouse model (BALB/c-nu/nu), primary s.c. tumors (HuH7; human HCC cells) were completely eradicated by rAd followed by treatment with ganciclovir. The same animals were subsequently rechallenged with HCC cells, tumor development was monitored, and the recruitment or activation of NK cells was analyzed immunohistochemically or by measuring IFN-γ mRNA expression. Tumor growth was markedly suppressed as compared with that in mice treated with a rAd expressing the HSV thymidine kinase gene alone (p < 0.001). Suppression of tumor growth was associated with the elevation of serum IL-12 and IL-18. During suppression, NK cells were recruited exclusively, and Th1 cytokine gene expression was enhanced in tumor tissues. The antitumor activity, however, was abolished either when the NK cells were inactivated with anti-asialo GM1 Ab or when anti-IL-12 and anti-IL-18 Abs were administered. These results indicate that suicide gene therapy, together with delivery of MCP-1, eradicates HCC cells and exerts prolonged NK cell-mediated antitumor effects in a model of HCC, suggesting a plausible strategy to prevent tumor recurrence.