Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNγ-induced apoptosis
Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNγ-induced apoptosis
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DOI：
10.1038/sj.gt.3301957
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发表时间：
2003-07-01
期刊：
影响因子：
5.1
通讯作者：
Melero, I
中科院分区：
文献类型：
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作者：
Mazzolini, G;Narvaiza, I;Melero, I
将编码IL-12的腺病毒和某些趋化因子联合注射到实验性肿瘤结节中能够诱导免疫介导的完全消退。在这项研究中，我们发现两种腺病毒的组合，一种编码IL-12和另一种编码MIP 3 α（AdCMVIL- 12+ AdCMVMIP 3 α），在治疗CT-26衍生的结肠癌方面非常成功。然而，在胰腺癌细胞系Panc 02产生的实验肿瘤中，这种联合治疗诱导了50%的肉眼完全消退，尽管1周内的局部复发几乎是恒定的。我们从这种复发性肿瘤中获得细胞系，发现从其接种物中获得的实验性恶性肿瘤在任何情况下都不适合用AdCMVIL-12+AdCMVMIP-3 α治疗。重要的是，复发细胞系对IFN γ体外诱导凋亡不敏感，与原始Panc 02细胞形成鲜明对比。通过复发细胞系与野生型Panc 02的cDNA阵列进行比较分析，揭示了重要数量的基因（383个），其表达水平被修饰超过两倍。这些变化分组在某些基因本体论的类别应该窝藏获得性选择性耐药IFN γ的机制解释。
Combined injections into experimental tumor nodules of adenovirus encoding IL-12 and certain chemokines are capable to induce immune-mediated complete regressions. In this study, we found that the combination of two adenoviruses, one encoding IL-12 and other MIP3alpha (AdCMVIL- 12+AdCMVMIP3alpha) was very successful in treating CT-26-derived colon carcinomas. However, in experimental tumors generated from the pancreatic carcinoma cell line Panc02 such combined treatment induces 50% of macroscopic complete regressions, although local relapses within 1 week are almost constant. We derived cell lines from such relapsing tumors and found that experimental malignancies derived from their inoculum were not amenable to treatment in any case with AdCMVIL-12+AdCMVMIP-3alpha. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNgamma, in clear contrast with the original Panc02 cells. Comparative analyses by cDNA arrays of relapsing cell lines versus wild-type Panc02 were performed revealing an important number of genes (383) whose expression levels were modified more than two-fold. These changes grouped in certain gene ontology categories should harbor the mechanistic explanations of the acquired selective resistance to IFNgamma.