Calreticulin exposure dictates the immunogenicity of cancer cell death
Abstract
Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.
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ER stress is a consequence of production of reactive oxygen species (ROS).
“It has been reported that the ER stress is a consequence of production of reactive oxygen species (ROS) [36]”
From Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma (2015) · cites this paper as [36]
CALR knockdown or defects in CALR exposure abolish ability of anthracycline-treated dying cancer cells to establish protective immunity in mice; recombinant CALR confers immunogenic properties to non-immunogenic RCD.
“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 [865]
Six DAMPs have been mechanistically linked to perception of RCD as immunogenic: CALR, ATP, HMGB1, type I IFN, cancer cell-derived nucleic acids, and ANXA1.
“So far, six DAMPs have been mechanistically linked to the perception of RCD as immunogenic: (1) calreticulin (CALR) [865, 866], (2) ATP [867–869], (3) high-mobility group box 1 (HMGB1) [870–872], (4) type I IFN [854, 873, 874], (5) cancer cell-derived nucleic acids [864, 875], and (6) annexin A1 (ANXA1) [876].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [865]
During ICD, CALR translocates from ER to outer leaflet of plasma membrane.
“In the course of ICD, CALR translocates from the ER, where it is involved in the maintenance of Ca2+ homeostasis [877], to the outer leaflet of the plasma membrane [865, 866].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [865]
Some cytotoxic chemotherapeutic drugs such as anthracycline and oxaliplatin could induce immunogenic cell death and stimulate antitumor immune response.
“Besides, some cytotoxic chemotherapeutic drugs such as anthracycline and oxaliplatin could induce immunogenic cell death and stimulate antitumor immune response [33, 34].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [33]
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- Authors
- Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G. M., Apetoh, L., Perfettini, J.-L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., Métivier, D., Larochette, N., van Endert, P., Ciccosanti, F., Piacentini, M., Zitvogel, L., & Kroemer, G.
- Affiliations
- Inserm (FR)
- Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT)
- University of Rome Tor Vergata (IT)
- ORCID
- Venue
- Nature Medicine
- Published
- 2006-12-24
- Volume
- 13
- Issue
- 1
- Pages
- 54-61
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2016612145
- Cited by
- 3,216
- References
- 36
- Citations by year
- 2026: 199 · 2025: 196 · 2024: 194 · 2023: 257 · 2022: 240 · 2021: 246 · 2020: 240 · 2019: 190 · 2018: 178 · 2017: 158 · 2016: 131 · 2015: 157 · 2014: 114 · 2013: 144 · 2012: 128
- FWCI
- 31.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- calreticulin, immunogenic cell death, dendritic cell phagocytosis, protein phosphatase 1, GADD34, etoposide, mitomycin C, antitumor immunity, immunogenic chemotherapy, cancer cell death
- MeSH terms
- Animals, Antigens, Differentiation, Antineoplastic Agents, Cell Membrane, Colonic Neoplasms, Dendritic Cells, Etoposide, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Experimental, Phagocytosis, Recombinant Proteins, Immunoblotting, Electrophoresis, Gel, Two-Dimensional, Mitomycin, Apoptosis, Cell Cycle Proteins, Anthracyclines, Protein Transport, RNA Interference, Calreticulin, Cell Line, Tumor, Mice, Protein Phosphatase 1
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