文章：

免疫原性细胞死亡和DAMPs在癌症治疗中的作用

Immunogenic cell death and DAMPs in cancer therapy

原文发布日期：2012-11-15

DOI: 10.1038/nrc3380

类型: Review Article

开放获取: 否

要点：

1. Damage-associated molecular patterns (DAMPs) are molecules that are secreted, released or surface exposed by dying, stressed or injured cells. DAMPs can function as either adjuvant or danger signals for the immune system. DAMPs such as surface-exposed calreticulin (CRT), secreted ATP and passively released high mobility group protein B1 (HMGB1) are vital for the immunogenic cell death (ICD) of cancer cells.
2. The pathway by which CRT is surface exposed depends on apoptotic stage: one molecular pathway might exclusively execute the trafficking of surface-exposed CRT, or several signalling pathways might coexist, and depending on the cell death stimulus, one signalling pathway could predominate.
3. The trafficking mechanism responsible for the secretion of ATP depends on the apoptotic stage and the type of stress or cell death stimulus that induces it. Moreover, both the mechanisms and the spatiotemporal pattern of ATP secretion from the dying cancer cells might be vital for establishing a suitable extracellular ATP gradient, which is required to engender its chemotactic or DAMP-like functions.
4. Extracellular HMGB1 is vital for the immunogenicity of ICD, but it is also associated with tumour progression. Evidence indicates that the multiple functions of extracellular HMGB1 might be attributed to its different redox states in a context-dependent manner. The in vivo importance of apoptosis-associated HMGB1 release, especially in the context of ICD in established tumours, needs further research.
5. The ability of selected cancer therapies to induce ICD depends on their ability to induce endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production (either in parallel or in tandem). Both ER stress and ROS production are essential components that instigate the intracellular danger signalling pathways that govern ICD.
6. ICD-associated immunogenicity is more effective if it is fostered by focused ROS-based ER stress (induced by type II ICD inducers such as hypericin-based photodynamic therapy (PDT)) rather than by secondary or collateral ER stress effects (as in the case of certain type I ICD inducers such as mitoxantrone and oxaliplatin).
7. Pre-existing therapy-resistant variants of tumour cells (formed as a result of cancer microevolution) pose an important problem for the therapeutic use of ICD inducers and ICD-associated danger signalling: ideally, ICD-mediating therapies need to overcome hurdles such as therapy-resistant microevolution in cancer. Future research needs to consider a treatment that is based on combinations of ICD inducers that could be applied simultaneously in order to reduce the probability of resistance arising. Alternatively, an ideal ICD inducer could be developed that targets several pathways. Of the current ICD inducers, those that have most of the ideal properties include mitoxantrone, hypericin-PDT, shikonin, cardiac glycosides and bortezomib.

要点翻译：

1. 损伤相关分子模式（DAMPs）是垂死、应激或受损细胞分泌、释放或表面暴露的分子。DAMPs可作为免疫系统的佐剂或危险信号。诸如表面暴露钙网蛋白（CRT）、分泌的ATP及被动释放的高迁移率族蛋白B1（HMGB1）等DAMPs，对癌细胞的免疫原性细胞死亡（ICD）至关重要。
2. CRT表面暴露的途径取决于凋亡阶段：可能仅由单一分子通路执行其转运，或多个信号通路共存，且根据细胞死亡刺激类型，某一信号通路可能占主导地位。
3. 负责ATP分泌的转运机制取决于凋亡阶段及诱导它的应激或细胞死亡刺激类型。此外，垂死癌细胞分泌ATP的机制和时空模式对于建立适宜的细胞外ATP梯度可能至关重要，该梯度是其产生趋化性或DAMP样功能所必需的。
4. 细胞外HMGB1对ICD的免疫原性至关重要，但也与肿瘤进展相关。证据表明细胞外HMGB1的多重功能可能与其在不同微环境下的氧化还原状态差异有关。凋亡相关HMGB1释放的体内重要性，尤其在已形成肿瘤的ICD背景下，尚需进一步研究。
5. 特定癌症疗法诱导ICD的能力取决于其诱导内质网（ER）应激和活性氧（ROS）产生的能力（并行或串联）。ER应激与ROS产生均是启动调控ICD的细胞内危险信号通路的核心要素。
6. 若由聚焦性ROS介导的ER应激（如II型ICD诱导剂金丝桃素为基础的光动力疗法PDT所诱导）推动ICD相关免疫原性，其效果优于继发性或伴随性ER应激效应（如I型ICD诱导剂米托蒽醌和奥沙利铂的情形）。
7. 由肿瘤细胞癌性微进化形成的预存耐药变异体，对ICD诱导剂及ICD相关危险信号的临床应用构成重要挑战：理想情况下，介导ICD的疗法需克服诸如癌症耐药微进化等障碍。未来研究需考虑联合应用多种ICD诱导剂以降低耐药发生概率。或可开发能靶向多条通路的理想ICD诱导剂。现有ICD诱导剂中，最接近理想特性的包括米托蒽醌、金丝桃素-PDT、紫草素、强心苷和硼替佐米。

英文摘要：

Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death (ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD.

摘要翻译： 

尽管曾认为凋亡细胞被快速吞噬后会经历一种不触发免疫应答的“静默死亡”，但近年来出现了“免疫原性细胞死亡（ICD）”的新概念。ICD 的免疫原性特征主要由损伤相关分子模式（DAMPs）介导，包括暴露在细胞表面的钙网蛋白（CRT）、分泌的 ATP 以及释放的高迁移率族蛋白 B1（HMGB1）。多数 DAMPs 可被模式识别受体（PRRs）识别。本综述探讨了内质网（ER）应激与活性氧（ROS）在调控濒死癌细胞免疫原性中的作用，以及治疗耐药性癌症的微观进化对 ICD 的影响。

原文链接：

Immunogenic cell death and DAMPs in cancer therapy