Calreticulin exposure dictates the immunogenicity of cancer cell death
Calreticulin exposure dictates the immunogenicity of cancer cell death
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DOI：
10.1038/nm1523
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发表时间：
2007-01-01
期刊：
影响因子：
82.9
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Obeid, Michel;Tesniere, Antoine;Kroemer, Guido
安东环素处理的肿瘤细胞在诱导抗癌免疫反应方面特别有效，而其他DNA损伤剂，如依托泊苷和丝裂霉素C不能诱导免疫原性细胞死亡。在这里，我们展示了蒽环素诱导钙网织蛋白(CRT)快速、凋亡前移位到细胞表面。阻断或敲除CRT可抑制小鼠树突状细胞对经蒽环素处理的肿瘤细胞的吞噬作用，并使其免疫原性丧失。通过抑制蛋白磷酸酶1/Gadd34复合体来模拟蒽环素诱导的CRT易位。重组CRT或蛋白磷酸酶1/Gadd34抑制剂可恢复依托泊苷和丝裂霉素C诱导的细胞死亡的免疫原性，并增强其体内抗肿瘤作用。这些数据确定CRT是决定抗癌免疫反应的关键特征，并描绘了一种可能的免疫原性化疗策略。
Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.