The DOI matches its Crossref record; 73 of the 76 references it cites were found in a registry or an index.
A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death
Open accessAbstract
Surface-exposed calreticulin (ecto-CRT) and secreted ATP are crucial damage-associated molecular patterns (DAMPs) for immunogenic apoptosis. Inducers of immunogenic apoptosis rely on an endoplasmic reticulum (ER)-based (reactive oxygen species (ROS)-regulated) pathway for ecto-CRT induction, but the ATP secretion pathway is unknown. We found that after photodynamic therapy (PDT), which generates ROS-mediated ER stress, dying cancer cells undergo immunogenic apoptosis characterized by phenotypic maturation (CD80(high), CD83(high), CD86(high), MHC-II(high)) and functional stimulation (NO(high), IL-10(absent), IL-1β(high)) of dendritic cells as well as induction of a protective antitumour immune response. Intriguingly, early after PDT the cancer cells displayed ecto-CRT and secreted ATP before exhibiting biochemical signatures of apoptosis, through overlapping PERK-orchestrated pathways that require a functional secretory pathway and phosphoinositide 3-kinase (PI3K)-mediated plasma membrane/extracellular trafficking. Interestingly, eIF2α phosphorylation and caspase-8 signalling are dispensable for this ecto-CRT exposure. We also identified LRP1/CD91 as the surface docking site for ecto-CRT and found that depletion of PERK, PI3K p110α and LRP1 but not caspase-8 reduced the immunogenicity of the cancer cells. These results unravel a novel PERK-dependent subroutine for the early and simultaneous emission of two critical DAMPs following ROS-mediated ER stress.
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“In line with a key role of CALR in the immunogenicity of RCD, the RNAi-mediated knockdown of CALR as well as natural defects in the CALR exposure pathway reportedly abolish the ability of dying cancer cells succumbing to anthracyclines to establish protective immunity in mice, whereas the exogenous provision of recombinant CALR confers immunogenic properties to otherwise non-immunogenic variants”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [883]
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Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
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Metadata
- Authors
- Garg, A. D., Krysko, D. V., Verfaillie, T., Kaczmarek, A., Ferreira, G. B., Marysael, T., Rubio, N., Firczuk, M., Mathieu, C., Roebroek, A. J. M., Annaert, W., Golab, J., de Witte, P., Vandenabeele, P., & Agostinis, P.
- Affiliations
- KU Leuven (BE)
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Agostinis, Patrizia
- ORCID
- Venue
- The EMBO Journal
- Published
- 2012-01-17
- Volume
- 31
- Issue
- 5
- Pages
- 1062-1079
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC3298003
- OpenAlex
- W1942176190
- Cited by
- 800
- References
- 76
- Citations by year
- 2026: 43 · 2025: 46 · 2024: 50 · 2023: 80 · 2022: 74 · 2021: 74 · 2020: 72 · 2019: 54 · 2018: 53 · 2017: 45 · 2016: 49 · 2015: 53 · 2014: 46 · 2013: 35 · 2012: 25
- FWCI
- 24.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- University of Alberta
- European Commission (200767)
- Fundacja na rzecz Nauki Polskiej
- Fonds De La Recherche Scientifique - FNRS
- Fonds Wetenschappelijk Onderzoek (G.0529.08)
- KU Leuven (GOA/11/009)
- Universiteit Gent (01M00709)
- Servier
- Vlaamse regering (BOF09/01M00709)
- European Regional Development Fund (POIG. 01.01.02-00-008/08)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- calreticulin, ATP release, immunogenic cancer cell death, photodynamic therapy, reactive oxygen species, endoplasmic reticulum stress, PERK, phosphatidylinositol 3-kinase, damage-associated molecular patterns, dendritic cell maturation, antitumor immunity, caspase-8, eIF2α phosphorylation, secretory pathway
- MeSH terms
- CD83 Antigen, Adenosine Triphosphate, Histocompatibility Antigens Class II, Cell Line, Dendritic Cells, Endoplasmic Reticulum, Humans, Immunoglobulins, Membrane Glycoproteins, Neoplasms, Antigens, CD, Cell Death, Photosensitizing Agents, Reactive Oxygen Species, B7-1 Antigen, Calreticulin, B7-2 Antigen
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