title: Sensitivity of cervical carcinoma cells to vesicular stomatitis virus-induced oncolysis: potential role of human papilloma virus infection.
abstract: High-risk carcinogenic subtypes of human papilloma virus (HPV) are associated with the development of squamous cell carcinomas of the cervix (CC) and a subset of head and neck (HNSCC). Recurrent metastatic diseases of these sites display a dismal prognosis. Therefore, there is an urgent need to uncover innovative therapeutic strategies in this clinical setting. Oncolytic viruses, including vesicular stomatitis virus (VSV), were identified due to their ability to specifically target tumor cells that generally display defects in interferon (IFN) signaling. HPV expressed proteins can inhibit IFN signaling; therefore, HPV-infected cells may be particularly sensitive to VSV oncolysis. In this study, we evaluated the sensitivity of four CC (HPV+) and four HNSCC (HPV-) derived cell lines to VSV oncolysis. Interestingly, the CC cell lines were consistently more sensitive to VSV cytotoxicity than the HNSCC cell lines tested. Exogenous IFN addition or infection with two attenuated VSV variants that are more susceptible to IFN inhibition failed to attenuate VSV oncolysis in hypersensitive CC cell lines. Furthermore, the expression of HPV-E6, that inhibits IFN receptor signaling, in the VSV-resistant HNSCC cell line SCC25 attenuated VSV-induced IFN response and significantly enhanced VSV cytotoxicity. Finally, differential VSV infection and replication was confirmed in xenograft murine tumor models and explant tumor tissues from two patients with CC. Taken together, these results demonstrate that HPV-infected cells are susceptible to oncolytic virus therapy and that this approach may represent a novel therapeutic approach in HPV positive CC and HNSCC patients.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.forename: Nima
authors.initials: N
authors.lastname: Niknejad
authors.forename: Jiahu
authors.initials: J
authors.lastname: Wang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Auer
authors.forename: Johanne I
authors.initials: JI
authors.lastname: Weberpals
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D052161:Human papillomavirus 18 / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology; D030361:Papillomavirus Infections / Q000821:virology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology*
chemical_list: D007372:Interferons