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Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase/CB1954 is enhanced by high-level coexpression of heat shock protein 70

Cancer Gene Therapy volume 12, pages 560–571 (2005)Cite this article

Abstract

Gene-directed enzyme prodrug therapy (GDEPT) is a promising approach to local management of cancer through targeted chemotherapy. Killing localized tumors by GDEPT in a manner that induces strong antitumor cellular immune responses might improve local management and allow benefit in disseminated cancer. Here we evaluated the combination of nitroreductase (NTR)/CB1954 GDEPT with high-level expression of heat shock protein 70 (HSP70, a stress protein that can shuttle cytosolic peptides into antigen-presenting cells) for induction of antitumor immunity using adenovirus gene delivery in an aggressive and nonimmunogenic BALB/c syngeneic 4T1 breast cancer model. The mechanism of cell death and spectrum of stress proteins induced are likely to be important determinants of the resulting immune responses. We showed that NTR/CB1954 treatment of 4T1 cells gave both apoptotic and nonapoptotic killing. In vivo killing of 4T1 cells expressing NTR gave weak antitumor immunity and very limited induction of stress proteins including HSP70. High-level coexpression of HSP70 during NTR/CB1954-mediated killing of 4T1 cells in vivo gave much greater protection from tumor challenge (67% long-term survivors compared to 17%) and induced 4T1-specific cytotoxic T-cell responses. The enhancement of antitumor responses resulting from HSP70 coexpression was similar to that conferred by coexpression of GM-CSF.

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Abbreviations

ATCC:

American Type Culture Collection

bp:

base pairs

CD40-L:

CD40 ligand

IFN:

interferon

IL:

interleukin

MHC:

major histocompatibility complex

nt:

nucleotides

PER.C6:

human embryonic retina cells stably transformed with plasmid pIG.E1A.E1B clone 6

SV40:

Simian virus 40

TLR:

Toll-like receptor

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Acknowledgements

S Todryk acknowledges Science Foundation Ireland for support. We thank R Vile for supplying an HSP70 expression plasmid.

Author information

Author notes

  1. Christopher J Wrighton

    Present address: Institute for Pathology, Karl-Franzens-University, Auenbrugger- platz 25, A-8036, Graz, Austria

  2. Hakim A Djeha and Stephen M Todryk: These authors contributed equally to this work.

Authors and Affiliations

  1. ML Research, Keele University Science Park, Keele, Staffordshire, UK

    Hakim A Djeha, Christopher J Wrighton, Alistair S Irvine, Andrew Mountain & Kai S Lipinski

  2. Immune Regulation Research Group, Department of Biochemistry, Trinity College Dublin, Dublin, 2, Ireland

    Stephen M Todryk

  3. Kinexus Bioinformatics Corporation, Vancouver, British Columbia, Canada

    Steven Pelech

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  1. Hakim A Djeha
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Correspondence to Kai S Lipinski.

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Djeha, H., Todryk, S., Pelech, S. et al. Antitumor immune responses mediated by adenoviral GDEPT using nitroreductase/CB1954 is enhanced by high-level coexpression of heat shock protein 70. Cancer Gene Ther 12, 560–571 (2005). https://doi.org/10.1038/sj.cgt.7700807

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