Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity.
In attempting to develop effective anticancer immunotherapies, the relative ability of apoptotic cells to induce an immune response remains an important but controversial consideration. A novel gene-transfer approach was used by which rapid induction of pure apoptosis can be selectively achieved in a transfected tumor cell population following exposure to a semisynthetic dimerizing ligand, AP20187. Inoculation of BALB/c mice with apoptotic and viable 12B1-D1 leukemia cells, at a 12:1 ratio subcutaneously, led to early tumor growth. Heat stress up-regulated the expression of membrane heat shock proteins (HSP72 and HSP60) on apoptotic 12B1-D1 cells, and stressed apoptotic cells were capable of generating a T-cell-mediated specific antitumor response. Pulsing of stressed apoptotic leukemia cells onto syngeneic dendritic cells resulted largely in rejection of coinjected viable 12B1-D1 cells. Mice rejecting the primary 12B1-D1 inoculum were immune to the same but not to a different leukemia challenge. Our findings indicate that tumor immunogenicity is dependent on whether cells are stressed before apoptosis induction and suggest that the immune system is capable of distinguishing between stressed and nonstressed cells undergoing programmed cell death. (Blood. 2001;97:3505-3512)
Feng
H
H
Department of Pediatrics, Steele Memorial Children's Research Center, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.
Zeng
Y
Y
Whitesell
L
L
Katsanis
E
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D018834:Chaperonin 60 / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D006358:Hot Temperature; D007938:Leukemia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics
D018834:Chaperonin 60; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D022021:Tacrolimus Binding Proteins