Brain Tumor Research Center and Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12006-11. doi: 10.1073/pnas.1307935110. Epub 2013 Jun 10.
Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47Δ-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-γ release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47Δ-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model.
胶质母细胞瘤（世界卫生组织四级）是一种侵袭性成人脑肿瘤，尽管进行了手术、放疗和化疗，但仍不可避免地导致死亡。治疗失败归因于细胞异质性的组合，包括通常具有抗性的癌症干细胞亚群、异常血管生成和值得注意的免疫抑制。目前的临床前模型和治疗策略不能令人满意地结合或解决所有这些特征。在此，我们描述了一种鼠胶质母细胞瘤干细胞（GSC）模型，该模型在同基因免疫活性小鼠中重现了肿瘤异质性、侵袭性、血管生成和免疫抑制微环境，应该对一系列治疗研究有用。使用该模型，我们测试了一种经过基因工程改造的溶瘤单纯疱疹病毒，该病毒携带一种免疫调节细胞因子白细胞介素 12（G47-mIL12）。G47Δ-mIL12 在体外感染和复制类似于其无武装溶瘤单纯疱疹病毒对应物在小鼠 005 GSCs 中，而在体内，它显著提高了携带颅内 005 肿瘤的同基因小鼠的存活率。从机制上讲，G47-mIL12 的靶点不仅是 GSCs，还增加 IFN-γ 的释放，抑制血管生成，并减少肿瘤中调节性 T 细胞的数量。疗效的增加取决于 T 细胞，但不取决于自然杀伤细胞。总之，我们的研究结果表明，G47Δ-mIL12 为靶向 GSCs、肿瘤微环境和免疫系统提供了一种多方面的方法，在严格的胶质母细胞瘤模型中具有治疗益处。
