Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-κB mediated and supports innate and adaptive anti-tumour immune priming

Molecular Cancer

Research

Kevin Harrington¹  Lynette Steele²  Robin Prestwich²  Elizabeth Ilett²  Alan Melcher²  Fiona Errington²  Peter Selby²  Richard Vile³  Matt Coffey⁴  Hardev Pandha⁵ 

[1] Institute of Cancer Research, Centre for Cell and Molecular Biology, Chester Beatty Laboratories, London, UK;Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK;Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK;Molecular Medicine Program and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA;Oncolytics Biotech Inc, Calgary, Alberta, Canada;Postgraduate Medical School, University of Surrey, Guildford, UK;

关键词: Dendritic Cell;    Natural Killer Cell;    Melanoma Cell;    Newcastle Disease Virus;    Caffeic Acid Phenethyl Ester;   

DOI  :  10.1186/1476-4598-10-20

 received in 2010-09-07, accepted in 2011-02-21,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundAs well as inducing direct oncolysis, reovirus treatment of melanoma is associated with activation of innate and adaptive anti-tumour immune responses.ResultsHere we characterise the effects of conditioned media from reovirus-infected, dying human melanoma cells (reoTCM), in the absence of live virus, to address the immune bystander potential of reovirus therapy. In addition to RANTES, IL-8, MIP-1α and MIP-1β, reovirus-infected melanoma cells secreted eotaxin, IP-10 and the type 1 interferon IFN-β. To address the mechanisms responsible for the inflammatory composition of reoTCM, we show that IL-8 and IFN-β secretion by reovirus-infected melanoma cells was associated with activation of NF-κB and decreased by pre-treatment with small molecule inhibitors of NF-κB and PKR; specific siRNA-mediated knockdown further confirmed a role for PKR. This pro-inflammatory milieu induced a chemotactic response in isolated natural killer (NK) cells, dendritic cells (DC) and anti-melanoma cytotoxic T cells (CTL). Following culture in reoTCM, NK cells upregulated CD69 expression and acquired greater lytic potential against tumour targets. Furthermore, melanoma cell-loaded DC cultured in reoTCM were more effective at priming adaptive anti-tumour immunity.ConclusionsThese data demonstrate that the PKR- and NF-κB-dependent induction of pro-inflammatory molecules that accompanies reovirus-mediated killing can recruit and activate innate and adaptive effector cells, thus potentially altering the tumour microenvironment to support bystander immune-mediated therapy as well as direct viral oncolysis.

【 授权许可】

Unknown   
© Steele et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.