Our previous studies have demonstrated that the natural chaperone complexes of full-length
tumor protein Ags (e.g., gp100) and large
stress proteins (e.g., hsp110 and
grp170) with exceptional Ag-holding capabilities augment potent
tumor protective immunity. In this study, we assess the
peptide-interacting property of these large chaperones and, for the first time, compare the immunogenicity of the recombinant chaperone
vaccines targeting two forms of Ags (
protein versus
peptide). Both hsp110 and
grp170 readily formed complexes with antigenic
peptides under physiologic conditions, and the
peptide association could be further stimulated by heat shock. The large chaperones displayed similar but distinct
peptide-binding features compared with hsp70 and
grp94/gp96. Immunization with hsp110- or grp170-tyrosinase-related
protein 2 (TRP2(175-192))
peptide complexes effectively primed CD8(+) T cells reactive with TRP2-derived, MHC class I-restricted
epitope. However, the
tumor protective effect elicited by the TRP2(175-192)
peptide vaccine was much weaker than that achieved by full-length TRP2
protein Ag chaperoned by
grp170. Furthermore, immunization with combined chaperone
vaccines directed against two
melanoma protein Ags (i.e., gp100 and TRP2) significantly improved overall anti-
tumor efficacy when compared with either of the single Ag
vaccine. Lastly, treatment of
tumor-bearing mice with these dual Ag-targeted chaperone complexes resulted in an immune activation involving
epitope spreading, which was associated with a strong growth inhibition of the established
tumors. Our results suggest that high m.w. chaperones are superior to conventional chaperones as a
vaccine platform to deliver large
protein Ags, and provide a rationale for translating this recombinant chaperoning-based
vaccine to future clinical investigation.