title: The PERKs of damage-associated molecular patterns mediating cancer immunogenicity: From sensor to the plasma membrane and beyond.
abstract: Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are emerging as key adaptation mechanisms in response to loss of proteostasis, with major cell autonomous and non-autonomous functions impacting cancer progression and therapeutic responses. In recent years, vital physiological roles of the ER in maintenance of proteostasis, Ca(2+) signaling and trafficking through the secretory pathway have emerged. Some of these functions have been shown to be decisive for mobilizing certain signals from injured/dying cancer cells in response to certain anticancer treatments, toward the plasma membrane and ultimately emit them into the extracellular environment, where they may act as danger signals. The spatiotemporally defined emission of these signals, better known as damage-associated molecular patterns (DAMPs), distinguishes this type of cancer cell death from physiological apoptosis, which is tolerogenic in nature, thereby enabling these dying cancer cells to alert the immune system and "re-activate" antitumor immunity. The emission of DAMPs, decisive for immunogenic cell death (ICD) and which include the ER chaperone calreticulin and ATP, is reliant on a danger signaling module induced by certain assorted anticancer treatments through oxidative-ER stress. The main focus of this review is to discuss the emerging role of ER-stress regulated pathways and processes in danger signaling thereby regulating the cancer cell-immune cell interface by the extracellular emission of DAMPs. In particular, we discuss signaling contexts existing upstream and around PERK, a major ER-stress sensor in ICD context, which have not been emphatically discussed in the context of antitumor immunity and ICD up until now. Finally, we briefly discuss the pros and cons of targeting PERK in the context of ICD.
authors.affiliation: Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: A R
authors.initials: AR
authors.lastname: van Vliet
authors.affiliation: Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Martin
authors.affiliation: Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: A D
authors.initials: AD
authors.lastname: Garg
authors.affiliation: Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, KU Leuven - University of Leuven, Leuven, Belgium. Electronic address: patrizia.agostinis@med.kuleuven.be.
authors.forename: P
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: C576483:CALR protein, human; D037282:Calreticulin; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: Cancer; Damage-associated molecular patterns; ER stress; Immunogenic cell death; Trafficking pathways