ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death
ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death
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DOI：
10.4161/auto.25399
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发表时间：
2013-09-01
期刊：
影响因子：
13.3
通讯作者：
Agostinis, Patrizia
中科院分区：
文献类型：
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作者：
Garg, Abhishek D.;Dudek, Aleksandra M.;Agostinis, Patrizia
钙网蛋白表面暴露（ecto-CALR）、ATP分泌、树突状细胞（DC）的成熟和T细胞的刺激是抗癌治疗诱导的免疫原性细胞死亡（ICD）的先决条件。最近的证据表明，化疗诱导的自噬可能通过促进ATP分泌来积极调节ICD。我们最近发现金丝桃素介导的光动力疗法（Hyp-PDT）触发的基于活性氧（ROS）的内质网（ER）应激诱导真正的ICD。然而，Hyp-PDT诱导的自噬是否调节ICD尚未探讨。在这里，我们表明，与预期相反，减少癌细胞中的自噬（通过ATG 5敲低）不会改变Hyp-PDT后的ATP分泌。自噬减弱的癌细胞在Hyp-PDT后表现出增强的外CALR诱导，这与它们无法清除氧化损伤的蛋白质密切相关。此外，Hyp-PDT处理的癌细胞中的自噬衰减增加了它们诱导DC成熟、IL 6产生和CD 4（+）或CD 8（+）T细胞增殖的能力，这伴随IFNG产生。因此，我们的研究揭示了ROS诱导的自噬在削弱垂死癌细胞和免疫系统之间的功能相互作用中的作用，从而帮助逃避ICD先决条件或决定因素。
Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy-induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy-induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT-treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants.