%0 Journal Article
%T IRE1¦Á regulates macrophage polarization, PD-L1 expression, and tumor survival
%A Alyssa Batista
%A Alyssa Lew
%A Gonzalo Almanza
%A Hannah Carter
%A Jeffrey J. Rodvold
%A Jonathan Lin
%A Kristen Jepsen
%A Maurizio Zanetti
%A Stephen C. Searles
%A Su Xian
%A T. Cameron Waller
%A Takao Iwawaki
%J PLOS Biology: A Peer-Reviewed Open-Access Journal
%D 2020
%R 10.1371/journal.pbio.3000687
%X 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 (IRE1¦Á) 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 IRE1¦Á/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 IFN¦Ã signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1¦Á- 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 IRE1¦Á gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow¨Cderived macrophages with IRE1¦Á deletion lose the integrity of the gene connectivity characteristic of regulated IRE1¦Á-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1¦Á/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance
%K Macrophages
%K Gene expression
%K Cancers and neoplasms
%K Breast cancer
%K Malignant tumors
%K Bone marrow cells
%K RNA sequencing
%K Renal cancer
%U https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000687