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Stress-induced inflammation evoked by immunogenic cell death is blunted by the IRE1α kinase inhibitor KIRA6 through HSP60 targeting

Authors
  • Rufo, Nicole1, 2
  • Korovesis, Dimitris1
  • Van Eygen, Sofie1, 2
  • Derua, Rita1
  • Garg, Abhishek D.1
  • Finotello, Francesca3
  • Vara-Perez, Monica1, 2
  • Rožanc, Jan4, 5
  • Dewaele, Michael2, 1
  • de Witte, Peter A.1
  • Alexopoulos, Leonidas G.5, 6
  • Janssens, Sophie7
  • Sinkkonen, Lasse4
  • Sauter, Thomas4
  • Verhelst, Steven H. L.1, 8
  • Agostinis, Patrizia1, 2
  • 1 KU Leuven, Leuven, Belgium , Leuven (Belgium)
  • 2 VIB Center for Cancer Biology Research, Leuven, Belgium , Leuven (Belgium)
  • 3 Medical University of Innsbruck, Innsbruck, Austria , Innsbruck (Austria)
  • 4 University of Luxembourg, Belvaux, Luxembourg , Belvaux (Luxembourg)
  • 5 Science Park Demokritos, Athens, Greece , Athens (Greece)
  • 6 National Technical University of Athens, Zografou, Greece , Zografou (Greece)
  • 7 Ghent University, Ghent, Belgium , Ghent (Belgium)
  • 8 Leibniz Institute for Analytical Sciences ISAS, e.V., Dortmund, Germany , Dortmund (Germany)
Type
Published Article
Journal
Cell Death & Differentiation
Publisher
Nature Publishing Group UK
Publication Date
Aug 27, 2021
Volume
29
Issue
1
Pages
230–245
Identifiers
DOI: 10.1038/s41418-021-00853-5
Source
Springer Nature
Disciplines
  • article
License
Green

Abstract

Mounting evidence indicates that immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress favor proficient cancer cell-immune interactions, by stimulating the release of immunomodulatory/proinflammatory factors by stressed or dying cancer cells. UPR-driven transcription of proinflammatory cytokines/chemokines exert beneficial or detrimental effects on tumor growth and antitumor immunity, but the cell-autonomous machinery governing the cancer cell inflammatory output in response to immunogenic therapies remains poorly defined. Here, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated a NF-κB/AP-1-inflammatory stress response, which dissociated from both cell death and UPR. This stress-induced inflammation was specifically abolished by the IRE1α-kinase inhibitor KIRA6. Supernatants from immunogenic chemotherapy and KIRA6 co-treated cancer cells were deprived of proinflammatory/chemoattractant factors and failed to mobilize neutrophils and induce dendritic cell maturation. Furthermore, KIRA6 significantly reduced the in vivo vaccination potential of dying cancer cells responding to immunogenic chemotherapy. Mechanistically, we found that the anti-inflammatory effect of KIRA6 was still effective in IRE1α-deficient cells, indicating a hitherto unknown off-target effector of this IRE1α-kinase inhibitor. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry, and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the IKK-driven NF-κB pathway. In sum, our study unravels that HSP60 is a KIRA6-inhibitable upstream regulator of the NF-κB/AP-1-inflammatory stress responses evoked by immunogenic treatments. It also urges caution when interpreting the anti-inflammatory action of IRE1α chemical inhibitors.

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