title: 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.
authors.affiliation: ML Research, Keele University Science Park, Keele, Newcastle under Lyme, Staffordshire ST5 5SP, UK.
authors.forename: Hakim A
authors.initials: HA
authors.lastname: Djeha
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Todryk
authors.forename: Steven
authors.initials: S
authors.lastname: Pelech
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wrighton
authors.forename: Alistair S
authors.initials: AS
authors.lastname: Irvine
authors.forename: Andrew
authors.initials: A
authors.lastname: Mountain
authors.forename: Kai S
authors.initials: KS
authors.lastname: Lipinski
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001388:Aziridines / Q000627:therapeutic use*; D005260:Female; D041722:Genes, Transgenic, Suicide; D005822:Genetic Vectors / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D009601:Nitroreductases / Q000235:genetics*; D011355:Prodrugs / Q000627:therapeutic use*; D040901:Proteomics; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D001388:Aziridines; D018840:HSP70 Heat-Shock Proteins; D011355:Prodrugs; C100099:tretazicar; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009601:Nitroreductases