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Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells

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Abstract

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 μM 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-γ) 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.

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Acknowledgment

C.L.-L. Chiang is supported by a Cancer Research UK studentship.

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Authors and Affiliations

  1. Department of Immunology and Molecular Pathology, Division of Infection and Immunity, UCL, Windeyer Building, 46 Cleveland Street, W1T 4JF, London, UK

    Cheryl L.-L. Chiang, Ariel N. Rad, David R. Katz & Benjamin M. Chain

  2. Department of Oncology, UCL, London, UK

    Jonathan A. Ledermann

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  1. Cheryl L.-L. Chiang
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  2. Jonathan A. Ledermann
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  3. Ariel N. Rad
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  4. David R. Katz
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Correspondence to Benjamin M. Chain.

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Chiang, C.LL., Ledermann, J.A., Rad, A. et al. Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells. Cancer Immunol Immunother 55, 1384–1395 (2006). https://doi.org/10.1007/s00262-006-0127-9

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