Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells
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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DOI：
10.1007/s00262-006-0127-9
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发表时间：
2006-11-01
影响因子：
5.8
通讯作者：
Chain, Benjamin M.
中科院分区：
文献类型：
--
作者：
Chiang, Cheryl L-L.;Ledermann, Jonathan A.;Chain, Benjamin M.
背景：卵巢癌通常在缓解后复发，需要针对显微镜下残留疾病的新策略。一种方法是用负载有肿瘤细胞的树突状细胞激活肿瘤特异性细胞毒性T细胞。为了增强它们的免疫原性，通过用次氯酸（HOCl）氧化来杀死卵巢肿瘤细胞（SKOV 3，其表达两种充分表征的抗原HER-2/neu和MUC-1）。结果：60 μ M HOCl处理1小时，发现在所有SK-OV-3细胞中诱导坏死。氧化的但不是活的SK-0 V-3被单核细胞衍生的树突细胞快速摄取，并诱导部分树突细胞成熟。用氧化的SK-0 V-3（HLA-A2（-））负载从HLA-A2健康志愿者培养的树突状细胞，并与自体T细胞共培养。在另一轮抗原刺激后测试应答T细胞的特异性。在ELISPOT测定中，T细胞响应于免疫细胞抗原以及编码MUC-1和HER-2/neu HLA-A2限制性表位的肽产生干扰素-γ（IFN-γ），证明了细胞相关抗原的有效交叉呈递。相反，在用热灭活或HCl灭活的SK-0 V-3引发后没有观察到应答，表明HOCl氧化而不是细胞死亡/坏死本身增强了SK-0 V-3的免疫原性。最后，用氧化的SK-0 V-3刺激的T细胞未显示出与氧化的黑素瘤细胞的交叉反应，反之亦然，表明该反应是肿瘤类型特异性的。结论：用氧化的卵巢肿瘤细胞系免疫可能代表一种改进的治疗策略，以刺激多克隆抗肿瘤细胞免疫应答，从而延长卵巢癌的缓解。
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 (SKOV3, 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 mu M 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.