Dey Aditi, Zhang Yu, Castleton Anna Z, Bailey Katharine, Beaton Brendan, Patel Bella, Fielding Adele K
Cancer Institute, University College London, London, UK.
Department of Laboratory Medicine, Harvard Medical School and Children's Hospital Boston, Boston, Massachusetts, USA.
Mol Ther. 2016 Feb;24(1):184-92. doi: 10.1038/mt.2015.149. Epub 2015 Aug 17.
The mechanism by which oncolytic measles virus (MV) kills cancer cells remains obscure. We previously showed that neutrophils are involved in MV-mediated tumor regressions and become activated, upon MV infection. In the present study, we attempted to enhance the neutrophil response toward MV-infected tumor targets by generating an oncolytic MV-expressing human granulocyte colony-stimulating factor (MVhGCSF). Evaluating the effects in two different models of B-cell malignancy, we showed that depletion of neutrophils abrogated the MV therapeutic effect in an in vivo Raji-but not Nalm-6 tumor model. Next, we compared MVhGCSF with the unmodified backbone virus MVNSe. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. This finding was recapitulated by exogenously administered hGCSF. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. Our data suggest that a "one-size-fits-all" model of immune response to viral oncolysis is not appropriate, and each tumor target will need full characterization for the potential of both direct and indirect, innate immune responses to generate benefit.
溶瘤麻疹病毒（MV）杀死癌细胞的机制仍不清楚。我们之前表明，中性粒细胞参与MV介导的肿瘤消退，并在MV感染后被激活。在本研究中，我们试图通过构建表达人粒细胞集落刺激因子的溶瘤MV（MVhGCSF）来增强中性粒细胞对MV感染的肿瘤靶标的反应。在两种不同的B细胞恶性肿瘤模型中评估其效果，我们发现，在体内Raji肿瘤模型中，中性粒细胞的耗竭消除了MV的治疗效果，但在Nalm-6肿瘤模型中并非如此。接下来，我们将MVhGCSF与未修饰的主干病毒MVNSe进行了比较。在体内Raji模型中，MVhGCSF增强了MV的溶瘤能力，而在Nalm-6模型中，情况却出乎意料地相反。外源性给予hGCSF也得到了同样的结果。MVhGCSF在可被MV感染的CD46转基因小鼠模型中复制，血清中可检测到hGCSF水平，但无毒性。我们的数据表明，对病毒溶瘤的免疫反应采用“一刀切”的模式并不合适，每个肿瘤靶标都需要全面表征直接和间接先天免疫反应产生益处的潜力。
