Davidoff A M, Kimbrough S A, Ng C Y, Shochat S J, Vanin E F
Department of Surgery, St Jude Children's Research Hospital and University of Tennessee, Memphis 38105, USA.
J Pediatr Surg. 1999 May;34(5):902-6; discussion 906-7. doi: 10.1016/s0022-3468(99)90395-0.
Interleukin-12 (IL-12) is a cytokine with potent antitumor effects. The authors sought to assess its capacity to increase tumor immunogenicity when expressed by tumor cells in a murine model of neuroblastoma.
Syngeneic A/J mice were inoculated subcutaneously with 2 x 10(6) cells from a murine neuroblastoma-derived cell line (neuro-2a). In situ transduction of the neuroblastoma cells was achieved by intratumoral injection of an adenoviral vector encoding both subunits of the murine IL-12 heterodimer. Growth of the IL-12 gene-modified tumor cells was compared with untreated neuro-2a cells. Tumor immunity was assessed by rechallenging mice that had rejected their tumor with unmodified neuroblastoma cells. The contribution of cytotoxic T lymphocytes (CTLs) was evaluated through cytotoxicity assays.
Eighteen (72%) of 25 tumor-bearing mice treated with the mlL-12 adenoviral vector exhibited tumor regression, with 12 mice (48%) completely rejecting their tumors over 2 to 3 weeks. None of the mice that had rejected their tumor and were rechallenged with unmodified neuro-2a cells subsequently developed new tumors. Pooled splenocytes from mice rejecting their tumors showed significant tumor killing (>20% cytolysis) in vitro in 51Cr release assays.
Adenoviral-mediated IL-12 expression by tumor cells in a murine neuroblastoma model produced a significant antitumor response. Most treated tumors demonstrated at least transient regression, whereas many completely regressed. Cured mice exhibited protective immunity and CTL activity against the tumor. These data confirm the immunomodulatory efficacy of IL-12 as part of a vaccine-based antineuroblastoma strategy.
白细胞介素-12（IL-12）是一种具有强大抗肿瘤作用的细胞因子。作者试图在神经母细胞瘤小鼠模型中评估肿瘤细胞表达IL-12时增强肿瘤免疫原性的能力。
将同基因A/J小鼠皮下接种2×10⁶个源自小鼠神经母细胞瘤的细胞系（Neuro-2a）的细胞。通过瘤内注射编码小鼠IL-12异二聚体两个亚基的腺病毒载体实现神经母细胞瘤细胞的原位转导。将IL-12基因修饰的肿瘤细胞的生长与未处理的Neuro-2a细胞进行比较。通过用未修饰的神经母细胞瘤细胞再次攻击已排斥其肿瘤的小鼠来评估肿瘤免疫。通过细胞毒性试验评估细胞毒性T淋巴细胞（CTL）的作用。
用小鼠IL-12腺病毒载体治疗的25只荷瘤小鼠中有18只（72%）出现肿瘤消退，12只小鼠（48%）在2至3周内完全排斥其肿瘤。没有一只排斥其肿瘤并随后用未修饰的Neuro-2a细胞再次攻击的小鼠出现新肿瘤。来自排斥其肿瘤的小鼠的混合脾细胞在体外51Cr释放试验中显示出显著的肿瘤杀伤作用（>20%细胞溶解）。
在小鼠神经母细胞瘤模型中，腺病毒介导的肿瘤细胞表达IL-12产生了显著的抗肿瘤反应。大多数接受治疗的肿瘤至少表现出短暂消退，而许多肿瘤完全消退。治愈的小鼠表现出针对肿瘤的保护性免疫和CTL活性。这些数据证实了IL-12作为基于疫苗的抗神经母细胞瘤策略一部分的免疫调节功效。
