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* Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and
Austin Research Institute, Heidelberg, Victoria, Australia
We have developed a molecular chaperone-based tumor vaccine that reverses the immune tolerance of cancer cells. Heat shock protein (HSP) 70 extracted from fusions of dendritic (DC) and tumor cells (HSP70.PC-F) possess superior properties such as stimulation of DC maturation and T cell proliferation over its counterpart from tumor cells. More importantly, immunization of mice with HSP70.PC-F resulted in a T cell-mediated immune response including significant increase of CD8 T cells and induction of the effector and memory T cells that was able to break T cell unresponsiveness to a nonmutated tumor Ag and provide protection of mice against challenge with tumor cells. By contrast, the immune response to vaccination with HSP70-PC derived from tumor cells is muted against such nonmutated tumor Ag. HSP70.PC-F complexes differed from those derived from tumor cells in a number of key manners, most notably, enhanced association with immunologic peptides. In addition, the molecular chaperone HSP90 was found to be associated with HSP70.PC-F as indicated by coimmunoprecipitation, suggesting ability to carry an increased repertoire of antigenic peptides by the two chaperones. Significantly, activation of DC by HSP70.PC-F was dependent on the presence of an intact MyD88 gene, suggesting a role for TLR signaling in DC activation and T cell stimulation. These experiments indicate that HSP70-peptide complexes (PC) derived from DC-tumor fusion cells have increased their immunogenicity and therefore constitute an improved formulation of chaperone protein-based tumor vaccine.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Cancer Institute Grant R01 CA87057, the Susan G. Komen Breast Cancer Foundation, and by funding from Boston University School of Medicine.
2 Y.E. and A.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Jianlin Gong, Department of Medicine, Boston University School of Medicine, Room 309, 650 Albany Street, Boston, MA 02118. E-mail address: jgong{at}bu.edu
4 Abbreviations used in this paper: HSP, heat shock protein; DC, dendritic cell; WT, wild type; Tg, transgenic; KO, knockout; LN, lymph node; LNC, LN cell; ON, overnight; PEG, polyethylene glycol; RT, room temperature; PC, peptide complex; GA, geldanamycin; HS, heat shock treated.
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  S. Koido, E. Hara, S. Homma, M. Mitsunaga, A. Takahara, E. Nagasaki, H. Kawahara, M. Watanabe, Y. Toyama, S. Yanagisawa, et al. Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells J. Immunol., October 1, 2007; 179(7): 4874 - 4883. [Abstract] [Full Text] [PDF]
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