Oncolytic Effects of a Novel Influenza A Virus Expressing Interleukin-15 from the NS Reading Frame

van Rikxoort, Marijke and Michaelis, Martin and Wolschek, Markus and Muster, Thomas and Egorov, Andrej and Seipelt, Joachim and Doerr, Hans Wilhelm and Cinatl, Jindrich (2012) Oncolytic Effects of a Novel Influenza A Virus Expressing Interleukin-15 from the NS Reading Frame. PLoS ONE, 7 (5). e36506. ISSN 1932-6203. (The full text of this publication is not available from this repository)

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Official URL
http://dx.doi.org/10.1371/journal.pone.0036506

Abstract

Oncolytic influenza A viruses with deleted NS1 gene (delNS1) replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15) coding sequence into the viral NS gene segment (delNS1-IL-15). DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1) infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected) melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.

Item Type: Article
Subjects: Q Science
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 24 Oct 2012 15:47
Last Modified: 19 Mar 2013 13:35
Resource URI: http://kar.kent.ac.uk/id/eprint/31968 (The current URI for this page, for reference purposes)
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