Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells.
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.
Enomoto
Yutaka
Y
Department of Medicine, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118, USA.
Bharti
Ajit
A
Khaleque
Ad Abdul
AA
Song
Baizheng
B
Liu
Chunlei
C
Apostolopoulos
Vasso
V
Xing
Pei-xiang
PX
Calderwood
Stuart K
SK
Gong
Jianlin
J
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002459:Cell Fusion; D003713:Dendritic Cells / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000302:isolation & purification; D007110:Immunity, Active / Q000235:genetics; D007114:Immunization; D051379:Mice; D018345:Mice, Knockout; D018396:Mucin-1 / Q000032:analysis; D046912:Multiprotein Complexes / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D010446:Peptide Fragments / Q000032:analysis; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D046912:Multiprotein Complexes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010446:Peptide Fragments; D010455:Peptides; D051193:Toll-Like Receptors