1] Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan [2] Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [3] Department of Advanced Molecular and Cell Therapy, Kyushu University Hospital,Kyushu University, Fukuoka, Japan.
Cell Death Differ. 2014 Jan;21(1):39-49. doi: 10.1038/cdd.2013.84. Epub 2013 Jul 5.
Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.
细胞凋亡通常表现为形态上同质的实体,被认为基本上是非免疫原性的。然而,最近发现,在几种化疗药物和溶瘤病毒的作用下,凋亡的癌细胞死亡,也称为 1 型程序性细胞死亡(PCD),通过释放各种危险相关分子模式(DAMPs)而具有免疫原性。大量研究表明,两种不同类型的免疫原性细胞死亡(ICD)诱导剂,最近根据其在内质网(ER)应激中的不同作用进行分类,可以重新启动被肿瘤微环境抑制的免疫反应。事实上,最近的临床研究表明,几种免疫治疗方式,包括治疗性癌症疫苗和溶瘤病毒,但不包括常规化疗,最终会产生有益的结果,可能是因为它们诱导 ICD 的机制不同。此外,对癌细胞 PCD 的兴趣已经从其经典形式转移到涉及自噬性细胞死亡(ACD)、程序性坏死细胞死亡(坏死性凋亡)和细胞焦亡的新型形式,其中一些在抗癌治疗后具有免疫原性。在这篇综述中,我们简要概述了形态上不同的细胞死亡诱导的特征明确的 DAMPs,如钙网蛋白(CRT)暴露、高迁移率族蛋白 B1(HMGB1)和三磷酸腺苷(ATP)释放。在后一部分,我们的综述重点介绍了新兴的溶瘤病毒如何诱导不同形式的细胞死亡,以及溶瘤病毒治疗与环磷酰胺和其他免疫治疗方式的进一步免疫调节相结合如何促进树突状细胞(DC)介导的抗肿瘤免疫。因此,充分了解哪种 ICD 诱导剂如何引起多模态 ICD 变得越来越重要,这有助于设计合理的多模态抗癌方式,以最大限度地触发 ICD 引发的抗肿瘤免疫,并消除残留或转移的肿瘤,同时避免自身免疫性疾病。