Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit- (EIF2S1, better known as eIF2), the activation of autophagy, and a global arrest in transcription and translation
Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit- (EIF2S1, better known as eIF2), the activation of autophagy, and a global arrest in transcription and translation. of malignancy. annexin A1, calreticulin, cytotoxic T lymphocyte-associated protein 4, (recognized name: EIF2S1) eukaryotic translation initiation factor 2 subunit-, high-mobility group box 1, (recognized name: HSPA1A), heat-shock protein family A (Hsp70) member 1A, interferon, (recognized name: IL1B), interleukin 1 beta, (recognized name: IL17), interleukin 17, not available, (recognized name: PDCD1) programmed cell death 1. aAdapted from ref. 46, not including targeted anticancer brokers and extracorporeal photochemotherapy. Thus, the development of methodological methods and platforms for identifying novel ICD inducers should accelerate the development of next-generation anticancer therapeutics, ultimately improving the clinical management of a large populace of oncological patients. Main hallmarks of ICD ICD can be induced by different stressors, including but not limited to (1) intracellular pathogens66C68; (2) standard chemotherapeutics such as anthracyclines, DNA-damaging brokers, and proteasomal inhibitors50,69C72; (3) targeted anticancer brokers such as the tyrosine kinase inhibitor crizotinib, the epidermal growth factor receptor-specific monoclonal antibody cetuximab and poly-ADP-ribose polymerase (PARP) inhibitors59,73C76; and (4) numerous physical modalities, encompassing hypericin- and redaporfin-based photodynamic therapy, extracorporeal photochemotherapy, numerous forms of ionizing radiation, high hydrostatic pressure, and severe heat shock77C81. DAMPs emitted in the course of ICD include endoplasmic reticulum (ER) chaperones such as calreticulin (CALR) and heat-shock proteins (HSPs), which are exposed around the cell surface, the non-histone chromatin-binding protein high-mobility group box 1 (HMGB1), the cytoplasmic protein annexin A1 (ANXA1), and the ZLN024 small metabolite ATP that are liberated from dying cells into the extracellular PKBG space, as well as type I interferons (IFNs) that are released upon de novo synthesis38,82C84. DAMPs can be recognized by both the innate and adaptive immune systems via unique PRRs driving chemoattraction, homing, activation, and/or maturation, ultimately resulting in the cross-presentation of tumor antigens to CD8+ CTLs in the context of strong immunostimulation34,43. Other hallmarks of ICD include the phosphorylation of eukaryotic translation initiation factor 2 subunit- (EIF2S1, better known as eIF2), the activation of autophagy, and a ZLN024 global arrest in transcription and translation85C88. Importantly, not all ICD inducers activate the same stress responses and hence elicit the same molecular signals16. Thus, for instance, although autophagy is usually strictly required for anthracycline-driven malignancy cell death to be perceived as immunogenic86, the same does not hold true for the demise of malignancy cells exposed to ionizing radiation89 (Fig. ?(Fig.11). Open in a separate windows Fig. 1 Main hallmarks of ICD.Different inducers of immunogenic cell death (ICD) have been shown to elicit incompletely overlapping molecular signatures with respect to ICD biomarkers. This not only reinforces the need for the simultaneous assessment of multiple surrogate ICD biomarkers in the context of screening campaigns, but also identifies an originally unsuspected diversity in the molecular and cellular mechanisms supporting adaptive immunity downstream of danger signaling. ANXA1, annexin A1; CALR, calreticulin, CXCL10, C-X-C motif chemokine ligand 10; ECP, extracorporeal photochemotherapy; HHP, high hydrostatic pressure; HMGB1, high-mobility group box 1; IFN, interferon; IL-1 (recognized name: IL1B), interleukin 1 beta; IL-17 (standard name: IL17), interleukin 17; PDT, photodynamic therapy. Calreticulin CALR uncovered around the plasma membrane of malignant cells undergoing ICD serves as an eat-me transmission that facilitates the engulfment of dying cells or their corpses by DCs or their precursors, thus providing ZLN024 them with an abundant source of antigenic material90C93. The molecular mechanism ZLN024 underlying the ICD-associated exposure of CALR include (1) the phosphorylation of eIF2, accompanied by ZLN024 (2) a strong arrest of protein translation and (3) the activation of pro-apoptotic caspase 8 (CASP8), followed by the cleavage of B-cell receptor-associated protein 31 (BCAP31), the aggregation of the pro-apoptotic Bcl-2 family members BCL2-associated X protein (BAX) and BCL2-antagonist/killer 1 (BAK1) at the outer mitochondrial membrane, and (4) the vesicle-associated membrane protein 1 (VAMP1)- and synaptosome-associated protein 25 (SNAP25)-mediated anterograde transport to the Golgi apparatus and exocytosis94. Surface-exposed CALR binds to LDL-receptor-related protein 1 (LRP1, best known as CD91), which is the main ER chaperone-sensing PRR expressed by antigen-presenting cells including DCs95,96. CD91 ligation promotes the engulfment of cellular corpses and debris by a mechanism that depends on the GTPase Rac family small GTPase 1 (RAC1)78,95,97. Consistent with the key role of CALR exposure in the belief of cell death as immunogenic, CALR knockdown by RNA interference (RNAi), deletion by CRISPR/Cas9, or CALR blockade by neutralizing antibodies decreases the potency of ICD-mediated anticancer immune responses in a.