title: Attenuated, oncolytic, but not wild-type measles virus infection has pleiotropic effects on human neutrophil function.
abstract: We previously showed that neutrophils play a role in regression of human tumor xenografts in immunodeficient mice following oncolytic vaccine measles virus (MV-Vac) treatment. In this study, we sought, using normal human neutrophils, to identify potential neutrophil-mediated mechanisms for the attenuated MV-Vac induced effects seen in vivo, by comparison with those consequent on wild-type (WT-MV) infection. Both MV-Vac and WT-MV infected and replicated within neutrophils, despite lack of SLAM expression. In both cases, neutrophils survived longer ex vivo postinfection. Furthermore, MV-Vac (but not WT-MV) infection activated neutrophils and stimulated secretion of several specific antitumor cytokines (IL-8, TNF-α, MCP-1, and IFN-α) via induction of de novo RNA and protein synthesis. In addition, MV-Vac (but not WT-MV) infection caused TRAIL secretion in the absence of de novo synthesis by triggering release of prefabricated TRAIL, via a direct effect upon degranulation. The differences between the outcome of infection by MV-Vac and WT-MV were not entirely explained by differential infection and replication of the viruses within neutrophils. To our knowledge, this is the first demonstration of potential mechanisms of oncolytic activity of an attenuated MV as compared with its WT parent. Furthermore, our study suggests that neutrophils have an important role to play in the antitumor effects of oncolytic MV.
authors.affiliation: Department of Haematology, University College London, London, United Kingdom.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bella
authors.initials: B
authors.lastname: Patel
authors.forename: Aditi
authors.initials: A
authors.lastname: Dey
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ghorani
authors.forename: Lena
authors.initials: L
authors.lastname: Rai
authors.forename: Mohammed
authors.initials: M
authors.lastname: Elham
authors.forename: Anna Z
authors.initials: AZ
authors.lastname: Castleton
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
mesh_terms: D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008457:Measles / Q000276:immunology; D008459:Measles virus / Q000276:immunology*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D016207:Cytokines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014613:Vaccines, Attenuated