Oxidation of Ovarian Epithelial Cancer Cells by Hypochlorous Acid Enhances Immunogenicity and Stimulates T Cells that Recognize Autologous Primary Tumor

• Published in: Clinical cancer research Vol. 14; no. 15; pp. 4898 - 4907
• Main Authors: Chiang, Cheryl L-L, Ledermann, Jonathan A, Aitkens, Egla, Benjamin, Elizabeth, Katz, David R, Chain, Benjamin M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.08.2008
• Subjects: Aged; CD40 Antigens - biosynthesis; CD8-Positive T-Lymphocytes - metabolism; dendritic cells; Dendritic Cells - cytology; Dendritic Cells - metabolism; Female; HER-2/neu; HLA-A2 Antigen - metabolism; Humans; hypochlorous acid; Hypochlorous Acid - pharmacology; IFN-γ ELISpot; Leukocytes, Mononuclear - cytology; Middle Aged; Models, Biological; MUC1; Neoplasms, Glandular and Epithelial - metabolism; Ovarian carcinoma; Ovarian Neoplasms - metabolism; Oxidants - pharmacology; Oxygen - chemistry; Oxygen - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4899

Purpose: Hypochlorous acid, a product of neutrophil myeloperoxidase, is a powerful enhancer of antigen processing and presentation. In this study, we examine whether ovarian epithelial cells (SK-OV-3) exposed to hypochlorous acid can stimulate T cells from patients with ovarian epithelial cancer that recognize common tumor antigens as well as autologous tumor. Experimental Design: T cells from human leukocyte antigen (HLA)-A2 + and HLA-A2 − patients or healthy controls were stimulated with autologous dendritic cells cocultured with the generic ovarian tumor line SK-OV-3, previously exposed to hypochlorous acid. Results: Hypochlorous acid–treated SK-OV-3 cells drove expansion of CD8 + T cells from HLA-A2 + individuals, which recognized the HLA-A2–restricted tumor antigen epitopes of HER-2/neu (E75 and GP2) and MUC1 (M1.1 and M1.2). Up to 4.1% of the T cells were positive for the HER-2/neu KIFGSLAFL epitope using pentamer staining. Dendritic cells loaded with oxidized SK-OV-3 cells and further matured with CD40 agonistic antibody or monophosphoryl lipid A additionally induced CD4 + class II–restricted responses. Critically, T cells stimulated with mature oxidized SK-OV-3 (but not a control oxidized melanoma cell line) directly recognized autologous tumor cells isolated from patient ascites. Conclusions: Immunization with mature dendritic cells loaded with a generic oxidized tumor cell line stimulates a polyclonal antitumor response that recognizes autologous tumor. These findings suggest a new immunotherapeutic strategy to extend remission in ovarian cancer.