Abstract
Background
Intrinsic or environmental stresses trigger the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), leading to ER stress. To cope with this, cells have evolved an adaptive mechanism named the unfolded protein response (UPR) which is hijacked by tumor cells to develop malignant features. Glioblastoma (GB), the most aggressive and lethal primary brain tumor, relies on UPR to sustain growth. We recently showed that IRE1 alpha (referred to IRE1 hereafter), 1 of the UPR transducers, promotes GB invasion, angiogenesis, and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts a worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment toward monocytes/macrophages and neutrophils.Methods
We used human and mouse cellular models in which IRE1 was genetically or pharmacologically invalidated and which were tested in vivo. Publicly available datasets from GB patients were also analyzed to confirm our findings.Results
We showed that IRE1 signaling, through both the transcription factor XBP1s and the regulated IRE1-dependent decay controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, resulting in chemokine production and myeloid infiltration in tumors.Conclusions
Our work identifies a novel IRE1/UBE2D3 proinflammatory axis that plays an instrumental role in GB immune regulation.References
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Funding
Funders who supported this work.
European Regional Development Fund
Fondation pour la recherche Médicale (1)
Grant ID: EU H2020 MSCA ITN-675448
INCR
INSERM
Institut National du Cancer
Rennes Métropole
Région Bretagne
des Côtes d'Armor et du Morbihan (1)
Grant ID: MSCA RISE-734749
des Côtes d’Armor et du Morbihan (3)
Grant ID: MSCA RISE-734749
Grant ID: NSRF 2014–2020
Grant ID: 5002780
