Premium
A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death
Author(s) -
Garg Abhishek D,
Krysko Dmitri V,
Verfaillie Tom,
Kaczmarek Agnieszka,
Ferreira Gabriela B,
Marysael Thierry,
Rubio Noemi,
Firczuk Malgorzata,
Mathieu Chantal,
Roebroek Anton J M,
Annaert Wim,
Golab Jakub,
de Witte Peter,
Vandenabeele Peter,
Agostinis Patrizia
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.497
Subject(s) - biology , calreticulin , immunogenic cell death , secretion , programmed cell death , cancer , cancer research , immunology , microbiology and biotechnology , cancer cell , endoplasmic reticulum , apoptosis , biochemistry , genetics
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.