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eIF2α phosphorylation is pathognomonic for immunogenic cell death.

Lucillia Bezu1,2,3,4,5,6, Allan Sauvat2,3,4,5,6, Juliette Humeau1,2,3,4,5,6

  • 1Faculty of Medicine, University of Paris Sud, Kremlin-Bicêtre, France.

Cell Death and Differentiation
|January 24, 2018
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Anticancer drugs induce immunogenic cell death (ICD) by phosphorylating eIF2α, a key stress response. This specific eIF2α phosphorylation, not other ER stress signs, correlates with calreticulin exposure, a crucial ICD marker.

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Area of Science:

  • Oncology
  • Cellular Biology
  • Immunology

Background:

  • Anticancer chemotherapeutics can induce immunogenic cell death (ICD), triggering anticancer immune responses.
  • ICD involves calreticulin (CALR) translocation to the cell surface, facilitating tumor antigen presentation.
  • The endoplasmic reticulum (ER) stress response, including eIF2α phosphorylation, is implicated in cellular stress pathways.

Purpose of the Study:

  • To systematically investigate the ER stress response induced by anticancer chemotherapeutics.
  • To determine which ER stress markers correlate with ICD and CALR exposure.
  • To identify drug properties associated with ICD induction.

Main Methods:

  • In vitro and in vivo studies of anticancer chemotherapeutics on cancer cells and mouse models.
  • Analysis of eIF2α phosphorylation, ATF4 activation, XBP1s splicing, and ATF6 cleavage.
  • Correlation analysis between ER stress markers and CALR exposure.
  • Machine-learning approaches to identify drug physicochemical properties linked to ICD.

Main Results:

  • ICD inducers efficiently phosphorylated eIF2α but did not activate other ER stress pathways (ATF4, XBP1s, ATF6).
  • Only eIF2α phosphorylation correlated with CALR exposure across various chemotherapeutics.
  • eIF2α phosphorylation by mitoxantrone was mediated by EIF2AK3.
  • Machine learning identified eIF2α phosphorylation as the sole relevant ER stress response for ICD induction, predicting drug properties.

Conclusions:

  • eIF2α phosphorylation is a key, specific indicator of ER stress relevant to ICD.
  • This finding simplifies the identification of ICD-inducing anticancer drugs based on physicochemical properties.
  • eIF2α phosphorylation appears to be a pathognomonic characteristic of ICD.