IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival

PLoS Biology
Alyssa T BatistaMaurizio Zanetti

Abstract

In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages wi...Continue Reading

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Citations

Aug 22, 2020·Photochemical & Photobiological Sciences : Official Journal of the European Photochemistry Association and the European Society for Photobiology·Mladen KorbelikZdzislaw M Szulc
Nov 21, 2020·Nature Reviews. Cancer·Xi Chen, Juan R Cubillos-Ruiz
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Aug 3, 2021·Biochemical Society Transactions·Ana Sayuri Yamagata, Paula Paccielli Freire

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Methods Mentioned

BETA
protein folding
Flow cytometry
PCR
RNASeq
FACS
Protein Assay
transgenic

Software Mentioned

Flow JO ( Tree Star )
REACTOME
NanoDrop
iQue Screener
CellQuest Pro
statsmodels
CIBERSORT

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