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Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2

Cancer Gene Therapy volume 14, pages 773–780 (2007)Cite this article

Abstract

Dendritic cells (DC) perform an important role in the initiation of the immune response through the local secretion of inflammatory mediators within diseased tissue in response to Toll-like receptor (TLR) ligation. However, DC vaccine strategies fail to make use of this capability against cancer. To harness the TLR response capability of DC against cancer, we tested a series of recombinant genes for their ability to redirect DC function specifically against a tumor-associated antigen. Each gene encoded a cell surface chimeric protein made up of extracellular single-chain immunoglobulin anti-erbB2 linked to an intracellular TLR-signaling component composed of either myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1 (IRAK-1) or the cytoplasmic domain of TLR4. Each gene was expressed in the DC line, JAWS II, to a similar degree following retroviral transduction. However, only the chimera containing IRAK-1 was able to mediate interleukin-12 and tumor necrosis factor-α secretion. Since TLR engagement can also activate DC and enhance their ability to stimulate T cells, we ligated the chimeric anti-erbB2-IRAK-1 receptor and determined the effect on the stimulation of T cells. We found that JAWS II cells triggered through chimeric anti-erbB2-IRAK-1 displayed an enhanced ability to stimulate ovalbumin-specific OT-II CD4+ T cells. This first description of the generation of tumor-reactive DC may lead to the development of new cell-based vaccines that can act at both the tumor site to induce danger and at the lymph node to stimulate a specific T-cell response.

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Acknowledgements

This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC), the Cancer Council of Australia, the Bob Parker Memorial Trust and the Peter MacCallum Cancer Centre Foundation. MK is supported by a Career Development Award from the National Breast Cancer Foundation and NHMRC. PD is supported by an RD Wright Fellowship, NHMRC. YX is supported by a Peter Doherty Postdoctoral Fellowship from the NHMRC.

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Authors and Affiliations

  1. Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia

    Y Xu, P K Darcy & M H Kershaw

  2. Department of Pathology, University of Melbourne, Melbourne, Australia

    Y Xu, P K Darcy & M H Kershaw

Authors
  1. Y Xu
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  2. P K Darcy
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  3. M H Kershaw
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Correspondence to M H Kershaw.

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YX designed, performed the research and analyzed data; PD contributed vital new reagents; MK designed the research and wrote the paper.

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Xu, Y., Darcy, P. & Kershaw, M. Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2. Cancer Gene Ther 14, 773–780 (2007). https://doi.org/10.1038/sj.cgt.7701073

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