The Role of Neutrophils in Measles Virus-mediated Oncolysis Differs Between B-cell Malignancies and Is Not Always Enhanced by GCSF.
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.
Cancer Institute, University College London, London, UK.
Aditi
A
Dey
Department of Laboratory Medicine, Harvard Medical School and Children's Hospital Boston, Boston, Massachusetts, USA.
Yu
Y
Zhang
Department of Haemato-Oncology, St. Bartholomews Hospital, West Smithfield, London, UK.
Anna Z
AZ
Castleton
Cancer Institute, University College London, London, UK.
Katharine
K
Bailey
Cancer Institute, University College London, London, UK.
Brendan
B
Beaton
Barts Cancer Institute, The London School of Medicine, Queen Mary University of London, London, UK.
Bella
B
Patel
Cancer Institute, University College London, London, UK.
Adele K
AK
Fielding
D000818:Animals; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008459:Measles virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
D016179:Granulocyte Colony-Stimulating Factor