Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice
Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice
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DOI：
10.1126/science.1208347
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发表时间：
2011-12-16
期刊：
影响因子：
56.9
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Michaud, Mickael;Martins, Isabelle;Kroemer, Guido
当抗肿瘤化疗诱导免疫原性细胞死亡，从而引发抗癌免疫反应时，它们特别有效。在这里，我们证明了自噬，这在癌症中通常是无效的，对于化疗诱导的细胞死亡是必要的，但对于它的免疫原性是必需的。作为对化疗的反应，癌症具有自噬能力，但不是自噬缺陷，它会吸引树突状细胞和T淋巴细胞进入肿瘤床。抑制自噬抑制死亡的肿瘤细胞释放三磷酸腺苷(ATP)。相反，抑制细胞外ATP降解酶增加了自噬缺陷肿瘤细胞周围的ATP，重建了免疫细胞的募集，并恢复了化疗反应，但仅限于免疫活性宿主。因此，自噬对于死亡细胞的免疫原性释放ATP是必不可少的，当自噬被禁用时，细胞外ATP浓度的增加提高了抗肿瘤化疗的疗效。
Antineoplastic chemotherapies are particularly efficient when they elicit immunogenic cell death, thus provoking an anticancer immune response. Here we demonstrate that autophagy, which is often disabled in cancer, is dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent, but not autophagy-deficient, cancers attracted dendritic cells and T lymphocytes into the tumor bed. Suppression of autophagy inhibited the release of adenosine triphosphate (ATP) from dying tumor cells. Conversely, inhibition of extracellular ATP-degrading enzymes increased pericellular ATP in autophagy-deficient tumors, reestablished the recruitment of immune cells, and restored chemotherapeutic responses but only in immunocompetent hosts. Thus, autophagy is essential for the immunogenic release of ATP from dying cells, and increased extracellular ATP concentrations improve the efficacy of antineoplastic chemotherapies when autophagy is disabled.