Targeted immunotherapy using reconstituted chaperone complexes of heat shock protein 110 and melanoma-associated antigen gp100.
This report defines a novel approach to heat shock protein vaccine formulation that takes advantage of the chaperoning property of heat shock protein hsp110 to efficiently bind a large protein substrate (specifically, human melanoma-associated antigen gp100) during heat shock. We demonstrate that hsp110 can form chaperone complexes with gp100 and prevent heat-induced aggregation of gp100. The resultant natural hsp110-gp100 complexes are strongly immunogenic as determined by their ability to elicit an antigen-specific IFN-gamma production and a cytotoxic T-cell response. Immunization with the hsp110-gp100 complex protected mice against subsequent challenge with human gp100-transduced B16 melanoma, which involves both CD4(+) and CD8(+) T-cell populations. Administration of the hsp110-gp100 vaccine also significantly suppressed the growth of established tumors in a therapeutic model. Furthermore, the hsp110-gp100 chaperone complex exhibited inhibitory effects on the progression of wild-type B16 tumor, suggesting that the induced immune response by human gp100 cross-reacts with mouse gp100. More importantly, the antitumor response obtained with the hsp110-gp100 complex is more potent than that obtained using Complete Freund's Adjuvant with gp100, whereas no response was observed against mouse hsp110 itself. Thus, the use of hsp110 to form natural chaperone complexes with tumor protein antigens such as gp100 represents a powerful approach to therapeutic vaccine formulation with significant potential for clinical application.
Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Xiang-Yang
XY
Wang
Xing
X
Chen
Masoud H
MH
Manjili
Elizabeth
E
Repasky
Robert
R
Henderson
John R
JR
Subjeck
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D002455:Cell Division / Q000276:immunology; D005260:Female; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D016233:Immunotherapy, Active / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use; D058951:gp100 Melanoma Antigen
D019496:Cancer Vaccines; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C490783:Hsp105 protein, mouse; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D014614:Vaccines, Synthetic; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma