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.