Enhanced Immunogenicity of Heat Shock Protein 70 Peptide Complexes from Dendritic Cell-Tumor Fusion Cells

• Published in: Journal of Immunology 2006-11, Vol.177 (9), p.5946-5955
• Main Authors: Enomoto, Yutaka, Bharti, Ajit, Khaleque, Ad Abdul, Song, Baizheng, Liu, Chunlei, Apostolopoulos, Vasso, Xing, Pei-xiang, Calderwood, Stuart K, Gong, Jianlin
• Format: Article
• Language: English
• Subjects: Animals; Cancer Vaccines - immunology; Cell Fusion; Dendritic Cells - immunology; HSP70 Heat-Shock Proteins - immunology; HSP70 Heat-Shock Proteins - isolation & purification; Immunity, Active - genetics; Immunization; Mice; Mice, Knockout; Mucin-1 - analysis; Multiprotein Complexes - chemistry; Multiprotein Complexes - immunology; Multiprotein Complexes - isolation & purification; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - prevention & control; Peptide Fragments - analysis; Peptides - immunology; T-Lymphocytes - immunology; Toll-Like Receptors - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.9.5946

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.