Westcott Marlena M, Liu Jingfang, Rajani Karishma, D'Agostino Ralph, Lyles Douglas S, Porosnicu Mercedes
Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
J Virol. 2015 Aug;89(15):7944-54. doi: 10.1128/JVI.00757-15. Epub 2015 May 20.
Oncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-β and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-β, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-β in resistant HNSCC cells. When added exogenously, IFN-β was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -β was further supported by the finding that autocrine IFN-β but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -β differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells.
There has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-β, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-β, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.
溶瘤病毒（OV）优先杀死癌细胞，部分原因是它们在暴露于I型干扰素（IFN）时抗病毒反应存在缺陷。然而，一些肿瘤细胞的IFN反应性赋予了对OV治疗的抗性。人I型IFN包括一种IFN-β和多种IFN-α亚型，它们共享相同的受体，但能够差异诱导生物学反应。本文探讨了个体IFN亚型在促进肿瘤细胞对OV抗性中的作用。比较了两种已用于临床的人IFN，即IFN-α2a和IFN-β，在保护人头颈部鳞状细胞癌（HNSCC）细胞系免受水泡性口炎病毒（VSV）溶瘤方面的活性。HNSCC细胞系对VSV杀伤的敏感性各不相同。VSV感染诱导抗性HNSCC细胞中IFN-β的产生增加。当外源性添加时，IFN-β在保护HNSCC细胞免受VSV溶瘤方面比IFN-α2a显著更有效。相反，正常角质形成细胞和内皮细胞受到两种IFN亚型的同等保护。肿瘤细胞对IFN-α和-β的差异反应性进一步得到以下发现的支持：自分泌IFN-β而非IFN-α在持续VSV感染期间促进HNSCC细胞的存活。因此，IFN-α和-β对VSV溶瘤有不同影响，这证明了对用于与VSV疗法联合使用的IFN亚型进行评估和比较是合理的。将VSV与IFN-α2a配对可能通过抑制VSV在正常细胞中的复制而不相应抑制癌细胞，增强溶瘤VSV疗法对HNSCC的选择性。
溶瘤病毒的开发取得了很大进展。然而，一个主要问题是个体癌症对溶瘤病毒的敏感性各不相同。在许多情况下，这是由于它们产生和对干扰素（IFN）反应的差异。本文所述实验比较了头颈部鳞状细胞癌细胞系对两种IFN亚型，即IFN-α2a和IFN-β，在免受溶瘤水泡性口炎病毒影响方面的反应。我们发现，IFN-α2a对癌细胞的保护作用明显低于IFN-β，而正常细胞受到两种IFN的同等保护。这些结果表明，从治疗角度来看，将VSV与IFN-α2a配对可能会增强对癌细胞与正常细胞的选择性。
