Human Tumor Cells Killed by Anthracyclines Induce a Tumor-Specific Immune Response
Human Tumor Cells Killed by Anthracyclines Induce a Tumor-Specific Immune Response
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DOI：
10.1158/0008-5472.can-11-0950
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发表时间：
2011-07-15
期刊：
影响因子：
11.2
通讯作者：
Spisek, Radek
中科院分区：
文献类型：
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作者：
Fucikova, Jitka;Kralikova, Petra;Spisek, Radek
免疫原性细胞死亡的特征在于包括钙网蛋白和热休克蛋白的分子伴侣的早期表面暴露，其影响树突状细胞（DC）的成熟以及肿瘤抗原的摄取和呈递。还显示其特征在于高迁移率族蛋白1（HMGB1）的晚期释放，其通过Toll样受体4（TLR4）起作用并增强抗原从垂死肿瘤细胞向DC的呈递。大多数关于免疫原性肿瘤细胞死亡的数据使用小鼠模型获得。在这项研究中，我们研究了临床使用的化疗药物诱导人肿瘤细胞系和原发性肿瘤细胞免疫原性细胞死亡的能力。我们发现，只有蒽环类药物才能诱导钙网蛋白、HSP 70和HSP 90快速转运至细胞表面，并在处理后12小时释放HMGB 1。未成熟DC与免疫原性肿瘤细胞的相互作用导致肿瘤细胞摄取增加并诱导DC的中度表型成熟。负载杀伤肿瘤细胞的DC有效刺激肿瘤特异性IFN-γ产生T细胞。用杀死的免疫原性肿瘤细胞脉冲的DC也诱导了比用非免疫原性肿瘤细胞脉冲的DC显著更低数量的调节性T细胞。这些数据表明，人前列腺癌、卵巢癌和急性淋巴细胞白血病细胞与小鼠肿瘤细胞具有免疫原性细胞死亡的关键特征。这些数据还鉴定了蒽环类作为能够在敏感的人肿瘤细胞中诱导免疫原性细胞死亡的抗癌药物。Cancer Res; 71（14）; 4821 - 33. (C)2011年AACR。
Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-gamma-producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells. Cancer Res; 71(14); 4821-33. (C) 2011 AACR.