title: Success of measles virotherapy in ATL depends on type I interferon secretion and responsiveness.
abstract: Adult T cell leukemia/lymphoma (ATL) is a highly aggressive CD4+/CD25+ T-cell malignancy caused by human T cell lymphotropic virus type 1 (HTLV-1). Previous studies in the MET-1 cell/NOD/SCID mouse model of ATL demonstrated that MET-1 cells are very susceptible to measles virus (MV) oncolytic therapy. To further evaluate the potential of MV therapy in ATL, the susceptibility of several HTLV-1 transformed CD4+ T cell lines (MT-1, MT-2, MT-4 and C8166-45) as well as HTLV-1 negative CD4+ T cell lines (Jurkat and CCRF-CEM) to infection with MV was tested in vitro. All cell lines were permissive to MV infection and subsequent cell death, except MT-1 and CCRF-CEM cells which were susceptible and permissive to MV infection, but resistant to cell death. The resistance to MV-mediated cell death was associated with IFNβ produced by MT-1 and CCRF-CEM cells. Inhibition of IFNβ rendered MT-1 and CCRF-CEM cells susceptible to MV-mediated cell death. Cells susceptible to MV-induced cell death did not produce nor were responsive to IFNβ. Upon infection with Newcastle Disease Virus (NDV), MT-1 and CCRF-CEM but not the susceptible cell lines up-regulated pSTAT-2. In vivo, treatment of tumors induced by MT-1 cell lines which produce IFNβ demonstrated only small increases in mean survival time, while only two treatments prolonged mean survival time in mice with MET-1 tumors deficient in type I interferon production. These results indicate that type I interferon production is closely linked with the inability of tumor cells to respond to type I interferon. Screening of tumor cells for type I interferon could be a useful strategy to select candidate patients for MV virotherapy.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: M Parrula
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, OH, United States; Comprehensive Cancer Center, The Arthur James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH, United States.
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
authors.forename: Kristina
authors.initials: K
authors.lastname: Landes
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States.
authors.forename: Devra
authors.initials: D
authors.lastname: Huey
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States; Center for Retrovirus Research, The Ohio State University, Columbus, OH, United States; Comprehensive Cancer Center, The Arthur James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Lairmore
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States; Center for Retrovirus Research, The Ohio State University, Columbus, OH, United States; Comprehensive Cancer Center, The Arthur James Cancer Hospital and Research Institute, The Ohio State University, Columbus, OH, United States. Electronic address: niewiesk.1@osu.edu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000628:therapy*; D008459:Measles virus / Q000254:growth & development*; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D016019:Survival Analysis
chemical_list: D007370:Interferon Type I
keywords: HTLV; Leukemia; Lymphoma; Measles virus; Mouse model; Virotherapy