Induction of systemic antitumor immunity by gene transfer of mammalian heat shock protein 70.1 into tumors in situ.
Heat shock proteins (hsps) chaperone cytosolic peptides, forming complexes that stimulate antitumor immunity. Hsps facilitate signal 1 in the two-signal model of T-cell costimulation, whereas cell adhesion molecules such as B7.1 provide secondary (signal 2) costimulatory signals. B7.1 gene transfer into tumors in situ has been shown to eradicate small (<0.3 cm in diameter) tumors in mice, and induce systemic antitumor immunity, but is ineffective against larger tumors. We examine whether mammalian hsps, as facilitators of T-cell costimulation, also exhibit this ability, and whether simultaneously stimulating both signal 1 (hsp-facilitated antigen presentation) and signal 2 (B7.1-mediated costimulation) enhances antitumor immunity compared to that achieved with either monotherapy. Prophylactic vaccination of mice with an hsp preparation from an EL-4 lymphoma weakly retarded tumor growth, to the same extent as that achieved with a single EL-4-derived peptide (AQHPNAELL), previously shown to induce antitumor immunity establishing that a preparation of EL-4 hsp-peptide complexes has antitumor activity. Here we show that injection of rat hsp70.1 into mouse tumors in situ causes the complete eradication of tumors, and generates potent systemic antitumor immunity mediated by CD4+ and CD8+ T cells. Unexpectedly, simultaneous gene transfer of hsp70.1 and B7.1 compromised the efficacy of hsp-mediated tumor rejection--a problem which could be partially overcome by the timed delivery of hsp70.1 and B7.1. Thus, gene transfer of hsp70 into tumors can be employed to generate potent systemic antitumor immunity, but further consideration is required if this approach is to be successfully combined with immunotherapies employing other T-cell costimulators.
Rafiee
M
M
Department of Molecular Medicine, School of Medicine and Health Science, University of Auckland, Auckland, New Zealand.
Kanwar
J R
JR
Berg
R W
RW
Lehnert
K
K
Lisowska
K
K
Krissansen
G W
GW
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics* / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D015316:Genetic Therapy; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000276:immunology; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D018840:HSP70 Heat-Shock Proteins; D015800:Protozoan Proteins; C081884:heat-shock protein 70.1