Hsp110 over-expression increases the immunogenicity of the murine CT26 colon tumor.
Several studies have suggested a positive correlation between heat shock protein (hsp) expression and tumor immunogenicity. Independently, many studies have shown that hsp purified from tumors can be used as a tumor-specific vaccine. In this study, we have explored the connection between hsp expression and anti-tumor immunity by transducing murine CT26 colon carcinoma cells with the cDNA of a major hsp, i.e. hsp110. We have shown that over-expression of hsp110 has no effect on CT26 tumor cell growth in vitro, and does not inhibit their anchorage-independent growth capacity. However, in situ, hsp110 over-expressing CT26 tumor (CT26-hsp110) grew at a significantly reduced rate as compared to the wild-type CT26 tumor in immunocompetent mice. Moreover, immunization of mice with inactivated CT26-hsp110 cells significantly inhibited the growth of wild-type CT26 tumor. This immunity was associated with an increased frequency of tumor-specific T cells after vaccination. An in vivo antibody depletion assay demonstrated that inactivated CT26-hsp110 cells elicited anti-tumor responses involving CD8(+) T cells and natural killer (NK) cells, but not CD4(+) T cells. Lastly, the effect of the addition of granulocyte-macrophage colony stimulating factor (GM-CSF) to these vaccine formulations was determined. Mice immunized with irradiated CT26-hsp110 cells combined with GM-CSF-producing bystander cells revealed a complete inhibition of CT26 tumor growth, indicating a synergy between inactivated CT26-hsp110 vaccine activity and GM-CSF. These observations demonstrate that manipulation of hsp110 expression in tumors, specifically when combined with GM-CSF, represents a potentially powerful approach to cancer vaccine formulation.
Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Xiang-Yang
XY
Wang
Ying
Y
Li
Masoud H
MH
Manjili
Elizabeth A
EA
Repasky
Drew M
DM
Pardoll
John R
JR
Subjeck
D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000528:radiation effects; D014611:Vaccination
D019496:Cancer Vaccines; D018076:DNA, Complementary; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C490783:Hsp105 protein, mouse; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor