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.

在肿瘤微环境中，局部免疫失调部分是由巨噬细胞和树突状细胞驱动的，它们被极化成混合的促炎/免疫抑制表型。展开的蛋白质反应（UPR）正在成为这些事件的可能起源。在这里我们报告UPR的需要肌醇的酶1（IRE1α）分支直接参与体内和体外巨噬细胞的极化，包括白介素6（IL-6），IL-23，Arginase1的上调以及CD86和程序性死亡配体1（PD-L1）的表面表达。IRE1α/ X-box结合蛋白1（Xbp1）轴在药理学上被阻断或在基因上被删除的巨噬细胞，其极化和CD86和PD-L1的表达均显着降低，而这与IFNγ信号传导无关，提示巨噬细胞PD-L1调控的新机制。当植入B16.F10黑色素瘤细胞时，具有IRE1α-但不具有Xbp1缺陷的巨噬细胞的小鼠显示出比对照组更大的存活率。值得注意的是，我们发现IRE1α基因签名与CD274基因在人类肿瘤浸润巨噬细胞中的表达。RNA测序（RNASeq）分析表明，具有IRE1α缺失的骨髓衍生巨噬细胞丧失了受调控的IRE1α依赖性衰变（RIDD）的基因连通性特征的完整性以及激活CD274基因表达的能力。因此，IRE1α/ Xbp1轴驱动肿瘤微环境中巨噬细胞的极化，引发复杂的免疫失调，导致局部免疫监测失败。