Journal Article

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

Carter, Hannah, Iwawaki, Takao, Zanetti, Maurizio, Waller, T. Cameron, Searles, Stephen C., Jepsen, Kristen, Xian, Su, Lew, Alyssa, Batista, Alyssa, Almanza, Gonzalo, Rodvold, Jeffrey J., Lin, Jonathan

2020

Overview

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 with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activating transcription factor 1 / Animals / Antigen presentation / Apoptosis / B7-H1 Antigen - metabolism / Batista, Jeffrey / Bioinformatics / Biology / Biology and Life Sciences / Bone marrow / Cancer / CD11b Antigen - metabolism / CD86 antigen / Cell Line, Tumor / Cell Polarity / Cell Proliferation / Cell Survival / Cytomegalovirus / Dendritic cells / Endoribonucleases - metabolism / Enzymes / Gene deletion / Gene expression / Gene Expression Regulation, Neoplastic / Gene sequencing / Genotype & phenotype / Homeostasis / Humans / Immunology / Immunosurveillance / Inflammation / Inflammation - pathology / Inositol / Interleukin 23 / Interleukin 6 / Kinases / Laboratories / Linear Models / Macrophages / Macrophages - metabolism / Medicine / Medicine and Health Sciences / Melanoma / Mice, Inbred C57BL / Mice, Knockout / Myeloid Cells - metabolism / Neoplasms - metabolism / Neoplasms - pathology / PD-L1 protein / Phenotype / Phenotypes / Polarization / Protein folding / Protein Serine-Threonine Kinases - metabolism / Proteins / Research and analysis methods / Ribonucleic acid / RNA / Sensors / Surgical implants / Survival / Transcription factors / Tumors / Unfolded Protein Response / X-Box Binding Protein 1 - metabolism / γ-Interferon