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Dendritic cells infected with a vaccinia virus interleukin-2 vector secrete high levels of IL-2 and can become efficient antigen presenting cells that secrete high levels of the immunostimulatory cytokine IL-12

Cancer Gene Therapy volume 10, pages 591–602 (2003)Cite this article

Abstract

Dendritic cell (DC) therapies using DC presenting tumor antigen/s can induce CD8+ CTL that mediate tumor eradication, nonetheless many patients remain unresponsive. Thus, cytokine gene vectors applied to DC may amplify these responses. Herein, we examined the responses that monocyte-derived DC (at different maturational stages) make when infected with a vaccinia virus-interleukin-2 (VV-IL-2) vector in vitro. VV-IL-2-infected DC secreted significant levels of bioactive IL-2 and maintained their antigen presentation function. However, we show that DC are exquisitely sensitive to their local antigenic microenvironment, and that responses generated by one antigen can be altered by another. VV-IL-2 infection of immature DC led to DC activation (upregulation of CD80, CD86 and class II surface molecules) when the virus was propagated through xenogeneic, but not syngeneic, mammalian cells; these DC secreted IL-10 and tumor necrosis factor-α (TNF-α), but not IL-12. In contrast, after VV-IL-2 infection (regardless of their mammalian cellular context), IFNγ/LPS-matured DC inevitably downregulated their antigen presenting machinery. In conclusion, immunostimulatory DC can be generated by VV-IL-2, but this depends upon (i) infecting immature DC only, (ii) the mammalian cells through which the virus is prepared and (iii) individual donors; hence donors must be screened to assess their specific responses.

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Acknowledgements

This work was supported by grants from the NH&MRC, SGIC and ALF. We thank Jane Allan for her advice and supply of the control vaccinia virus construct, as well as Dr Matthew Wikstrom and the Lotteries Commission WA Flow Cytometry Unit for assistance with FACs analysis.

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Authors and Affiliations

  1. Department of Medicine, University of Western Australia, Perth, Australia

    Sutapa Mukherjee, John W Upham, Christine Bundell, Ivonne van Bruggen, Bruce WS Robinson & Delia J Nelson

  2. Division of Cell Biology, Viral Engineering Group, John Curtin School of Medical Research, Australian National University, Canberra, Australia

    Ian Ramshaw

  3. Western Australian Institute for Medical Research, Perth, Australia

    Bruce WS Robinson & Delia J Nelson

  4. School of Biomedical Sciences, Curtin University, Perth, Australia

    Delia J Nelson

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  1. Sutapa Mukherjee
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Correspondence to Delia J Nelson.

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Mukherjee, S., Upham, J., Ramshaw, I. et al. Dendritic cells infected with a vaccinia virus interleukin-2 vector secrete high levels of IL-2 and can become efficient antigen presenting cells that secrete high levels of the immunostimulatory cytokine IL-12. Cancer Gene Ther 10, 591–602 (2003). https://doi.org/10.1038/sj.cgt.7700604

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