Antitumor immune responses mediated by adenoviral gdept using nitroreductase/cb1954 is enhanced by high-level coexpression of heat shock protein 70

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. Access through your institution Buy or subscribe This is a preview of subscription

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TUMOR MODEL Article Open access 24 January 2024 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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for support. We thank R Vile for supplying an HSP70 expression plasmid. AUTHOR INFORMATION Author notes * Christopher J Wrighton Present address: Institute for Pathology,

Karl-Franzens-University, Auenbrugger- platz 25, A-8036, Graz, Austria * Hakim A Djeha and Stephen M Todryk: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * ML

Research, Keele University Science Park, Keele, Staffordshire, UK Hakim A Djeha, Christopher J Wrighton, Alistair S Irvine, Andrew Mountain & Kai S Lipinski * Immune Regulation Research

Group, Department of Biochemistry, Trinity College Dublin, Dublin, 2, Ireland Stephen M Todryk * Kinexus Bioinformatics Corporation, Vancouver, British Columbia, Canada Steven Pelech Authors

* Hakim A Djeha View author publications You can also search for this author inPubMed Google Scholar * Stephen M Todryk View author publications You can also search for this author inPubMed

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Correspondence to Kai S Lipinski. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 14 July 2004 * Published: 21 January 2005 * Issue Date: 01 June 2005 * DOI: https://doi.org/10.1038/sj.cgt.7700807 SHARE

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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * GDEPT * adenovirus * HSP70 * nitroreductase * immunotherapy