Necroptosis promotes autophagy-dependent upregulation of DAMP and results in immunosurveillance
Necroptosis promotes autophagy-dependent upregulation of DAMP and results in immunosurveillance
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DOI：
10.1080/15548627.2017.1386359
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Yang, Ning-Sun
中科院分区：
文献类型：
--
作者：
Lin, Sheng-Yen;Hsieh, Sung-Yuan;Yang, Ning-Sun
程序性坏死（程序性坏死）被认为是一种高度免疫原性的活动，通常通过损伤相关分子模式（DAMP）的释放来介导。有趣的是，增强的巨自噬/自噬活性常常伴随着坏死性凋亡。然而，自噬在坏死性凋亡的免疫原性中可能发挥的作用在很大程度上仍然不清楚。在本研究中，我们研究了植物化学紫草素诱导的自噬与紫草素诱导的肿瘤免疫原性坏死性凋亡之间可能的机制相关性。我们发现紫草素可以引发 RIPK1（受体 [TNFRSF] 相互作用丝氨酸苏氨酸激酶 1）和 RIPK3（受体相互作用丝氨酸苏氨酸激酶 3）依赖性坏死性凋亡，并伴有自噬增强。紫草素诱导的自噬可直接导致 DAMP 上调。与直觉相反，在释放的 ectoDAMP 和 ectoDAMP 中，只有后者被证明能够激活共培养的树突状细胞 (DC)。通过氯喹中断自噬流进一步上调 ectoDAMP 活性和由此产生的 DC 激活。对于潜在的临床应用，用已经用氯喹和紫草素预处理的肿瘤细胞处理的DC疫苗制剂进一步增强了4T1肿瘤的抗转移活性，并减少了阿霉素的有效剂量。因此，通过紫草素和氯喹共同治疗肿瘤细胞获得的增强的免疫原性和疫苗功效可能构成通过使用组合药物治疗开发癌症疫苗的令人信服的策略。
Programmed necrosis, necroptosis, is considered to be a highly immunogenic activity, often mediated via the release of damage-associated molecular patterns (DAMPs). Interestingly, enhanced macroautophagic/autophagic activity is often found to be accompanied by necroptosis. However, the possible role of autophagy in the immunogenicity of necroptotic death remains largely obscure. In this study, we investigated the possible mechanistic correlation between phytochemical shikonin-induced autophagy and the shikonin-induced necroptosis for tumor immunogenicity. We show that shikonin can instigate RIPK1 (receptor [TNFRSF]-interacting serine-threonine kinase 1)- and RIPK3 (receptor-interacting serine-threonine kinase 3)-dependent necroptosis that is accompanied by enhanced autophagy. Shikonin-induced autophagy can directly contribute to DAMP upregulation. Counterintuitively, among the released and ectoDAMPs, only the latter were shown to be able to activate the cocultured dendritic cells (DCs). Interruption of autophagic flux via chloroquine further upregulated ectoDAMP activity and resultant DC activation. For potential clinical application, DC vaccine preparations treated with tumor cells that were already pretreated with chloroquine and shikonin further enhanced the antimetastatic activity of 4T1 tumors and reduced the effective dosage of doxorubicin. The enhanced immunogenicity and vaccine efficacy obtained via shikonin and chloroquine cotreatment of tumor cells may thus constitute a compelling strategy for developing cancer vaccines via the use of a combinational drug treatment.