Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression.
In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.
Melcher
A
A
Imperial Cancer Research Fund Laboratory of Molecular Therapy, ICRF Oncology Unit, Imperial College of Science and Medicine, Hammersmith Hospital, London, UK.
Todryk
S
S
Hardwick
N
N
Ford
M
M
Jacobson
M
M
Vile
R G
RG
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis; D016923:Cell Death; D015179:Colorectal Neoplasms / Q000276:immunology*; D015774:Ganciclovir / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase
D000951:Antigens, Neoplasm; D000998:Antiviral Agents; D018840:HSP70 Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013937:Thymidine Kinase; D015774:Ganciclovir