Immunogenic cell death and DAMPs in cancer therapy

• Published in: Nature reviews. Cancer Vol. 12; no. 12; pp. 860 - 875
• Main Authors: Krysko, Dmitri V., Garg, Abhishek D., Kaczmarek, Agnieszka, Krysko, Olga, Agostinis, Patrizia, Vandenabeele, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2012; Nature Publishing Group
• Subjects: 631/250/1932; 631/80/86; 692/699/67/1059; 82; Adenosine Triphosphate - metabolism; Animals; Antineoplastic Agents - pharmacology; Apoptosis; ATP; Biomedical and Life Sciences; Biomedicine; Calreticulin; Calreticulin - metabolism; Cancer; Cancer cells; Cancer Research; Care and treatment; Cell death; Cell Death - immunology; Cellular signal transduction; Endoplasmic reticulum; Endoplasmic Reticulum - immunology; Endoplasmic Reticulum - metabolism; High mobility group proteins; HMGB1 protein; HMGB1 Protein - immunology; HMGB1 Protein - metabolism; Humans; Immune response; Immunogenicity; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Pattern recognition; Phagocytosis - immunology; Physiological aspects; Reactive oxygen species; Reactive Oxygen Species - immunology; Reactive Oxygen Species - metabolism; review-article
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc3380

Key Points 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. 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. 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. 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. 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. 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). 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. In recent years a new concept of immunogenic cell death (ICD) has emerged. In this Review, the authors discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and how this might relate to therapeutic intervention. 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.