Superior antitumor response induced by large stress protein chaperoned protein antigen compared with peptide antigen.
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.
Wang
Xiang-Yang
XY
Department of Human and Molecular Genetics, Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. xywang@vcu.edu
Sun
Xiaolei
X
Chen
Xing
X
Facciponte
John
J
Repasky
Elizabeth A
EA
Kane
John
J
Subjeck
John R
JR
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D006023:Glycoproteins / Q000276:immunology; D050957:HSP110 Heat-Shock Proteins / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006023:Glycoproteins; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; C098410:glucose-regulated protein 170; C500290:peptide SVYDFFVWL; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase