EIF2α phosphorylation as a biomarker of immunogenic cell death

Oliver Kepp, Michaela Semeraro, José Manuel Bravo-San Pedro, Norma Bloy, Aitziber Buqué, Xing Huang, Heng Zhou, Laura Senovilla, Guido Kroemer, Lorenzo Galluzzi

Research output: Contribution to journalReview articlepeer-review

97 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)86-92
Number of pages7
JournalSeminars in Cancer Biology
Volume33
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

Keywords

  • ATF4
  • Apoptosis
  • Autophagy
  • IRE1α
  • PERK
  • Heat-Shock Proteins/metabolism
  • Phosphorylation
  • Protein Biosynthesis
  • Humans
  • Signal Transduction/genetics
  • Epitopes/chemistry
  • Biomarkers/metabolism
  • Calreticulin/metabolism
  • Endoplasmic Reticulum Chaperone BiP
  • Eukaryotic Initiation Factor-2/metabolism
  • Animals
  • Antigen-Presenting Cells/cytology
  • Cell Membrane/metabolism
  • Endoplasmic Reticulum Stress
  • Cell Death
  • Mice
  • Endoplasmic Reticulum/metabolism

Fingerprint

Dive into the research topics of 'EIF2α phosphorylation as a biomarker of immunogenic cell death'. Together they form a unique fingerprint.

Cite this