Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells.
BACKGROUND
Ovarian cancer commonly relapses after remission and new strategies to target microscopic residual diseases are required. One approach is to activate tumor-specific cytotoxic T cells with dendritic cells loaded with tumor cells. In order to enhance their immunogenicity, ovarian tumor cells (SK-OV-3, which express two well-characterized antigens HER-2/neu and MUC-1) were killed by oxidation with hypochlorous acid (HOCl).


RESULTS
Treatment for 1 h with 60 microM HOCl was found to induce necrosis in all SK-OV-3 cells. Oxidized, but not live, SK-OV-3 was rapidly taken up by monocyte-derived dendritic cells, and induced partial dendritic cell maturation. Dendritic cells cultured from HLA-A2 healthy volunteers were loaded with oxidized SK-OV-3 (HLA-A2-) and co-cultured with autologous T cells. Responding T cells were tested for specificity after a further round of antigen stimulation. In ELISPOT assays, T cells produced interferon-gamma (IFN-gamma) in response to the immunizing cellular antigen, and also to peptides coding for MUC-1 and HER-2/neu HLA-A2 restricted epitopes, demonstrating efficient cross-presentation of cell-associated antigens. In contrast, no responses were seen after priming with heat-killed or HCl-killed SK-OV-3, indicating that HOCl oxidation and not cell death/necrosis per se enhanced the immunogenicity of SK-OV-3. Finally, T cells stimulated with oxidized SK-OV-3 showed no cross-reaction to oxidized melanoma cells, nor vice versa, demonstrating that the response was tumor-type specific.


CONCLUSIONS
Immunization with oxidized ovarian tumor cell lines may represent an improved therapeutic strategy to stimulate a polyclonal anti-tumor cellular immune response and hence extend remission in ovarian cancer.
Chiang
Cheryl L-L
CL
Department of Immunology and Molecular Pathology, Division of Infection and Immunity, UCL, Windeyer Building, 46 Cleveland Street, W1T 4JF, London, UK.
Ledermann
Jonathan A
JA
Rad
Ariel N
AN
Katz
David R
DR
Chain
Benjamin M
BM
D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology*; D005260:Female; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D013601:T-Lymphocytes / Q000166:cytology; D014184:Transplantation, Homologous
D010455:Peptides; D006997:Hypochlorous Acid; D007371:Interferon-gamma; D010100:Oxygen