eIF2α phosphorylation as a biomarker of immunogenic cell death.
Cancer cells exposed to some forms of chemotherapy and radiotherapy die while eliciting an adaptive immune response. Such a functionally peculiar variant of apoptosis has been dubbed immunogenic cell death (ICD). One of the central events in the course of ICD is the activation of an endoplasmic reticulum (ER) stress response. This is instrumental for cells undergoing ICD to emit all the signals that are required for their demise to be perceived as immunogenic by the host, and culminates with the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). In particular, eIF2α phosphorylation is required for the pre-apoptotic exposure of the ER chaperone calreticulin (CALR) on the cell surface, which is a central determinant of ICD. Importantly, phosphorylated eIF2α can be quantified in both preclinical and clinical samples by immunoblotting or immunohistochemistry using phosphoneoepitope-specific monoclonal antibodies. Of note, the phosphorylation of eIF2α and CALR exposure do not necessarily correlate with each other, and neither of these parameters is sufficient for cell death to be perceived as immunogenic. Nonetheless, accumulating data indicate that assessing the degree of phosphorylation of eIF2α provides a convenient parameter to monitor ICD. Here, we discuss the role of the ER stress response in ICD and the potential value of eIF2α phosphorylation as a biomarker for this clinically relevant variant of apoptosis.
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
Oliver
O
Kepp
Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1015, Paris, France.
Michaela
M
Semeraro
INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France.
José Manuel
JM
Bravo-San Pedro
INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France.
Norma
N
Bloy
INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France.
Aitziber
A
Buqué
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
Xing
X
Huang
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
Heng
H
Zhou
INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France.
Laura
L
Senovilla
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France. Electronic address: kroemer@orange.fr.
Guido
G
Kroemer
INSERM, U1138, Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie/Paris VI, Paris, France. Electronic address: deadoc@vodafone.it.
Lorenzo
L
Galluzzi
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism*; D037282:Calreticulin / Q000378:metabolism; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D000939:Epitopes / Q000737:chemistry; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D015398:Signal Transduction / Q000235:genetics
D015415:Biomarkers; C576483:CALR protein, human; D037282:Calreticulin; D000091342:Endoplasmic Reticulum Chaperone BiP; D000939:Epitopes; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins
ATF4; Apoptosis; Autophagy; IRE1α; PERK