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Immunology |
Department of Molecular and Cellular Biophysics [M. H. M., X-Y. W., X. C., Y. L., L. K., J. R. S.] and Department of Immunology [E. R.], Roswell Park Cancer Institute, Buffalo New York 14263, and Corixa Corporation, Seattle Washington 98104 [R. H.]
Several studies have shown that when purified from a tumor, certain heat shock proteins (HSPs) can function as effective vaccines against the same tumor by virtue of their ability to bind tumor-specific peptides. However, only a small fraction of the associated peptides would be expected to be immunogenic, in addition to which, the clinical application of this vaccine requires the availability of a surgical specimen of sufficient quantity for purification of the HSP. The present study describes a new approach for the development of natural HSP vaccines that do not have these limitations. This approach uses a recombinant HSP that is noncovalently bound to a recombinant tumor protein antigen by heat shock. HSP110 has been selected for this purpose, because it has been shown to be a highly efficient molecular chaperone in binding to large protein substrates. We show that a "natural chaperone complex" between HSP110 and the intracellular domain (ICD) of human epidermal growth factor receptor 2 protein (HER-2)/neu is formed by heat shock. This HSP110-ICD vaccine elicited both CD8+ and CD4+ T-cell responses against ICD as determined by an antigen-specific IFN-
production in an enzyme-linked immunospot assay (ELISPOT). In vivo depletion studies revealed that the CD8+ T-cell response was independent of CD4+ T-cell help. The HSP110-ICD complex also significantly enhanced ICD-specific antibody responses relative to that seen with ICD alone. No CD8+ T cell or antibody response was detected against HSP110. The use of recombinant HSP110 to form natural chaperone complexes with large protein antigens represents a new and powerful approach for the design of protein-targeted cancer vaccines.
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