Tumor cells are exposed to intrinsic and environmental challenges that trigger endoplasmic reticulum (ER) homeostasis alteration, in turn leading to ER stress. To cope with this, tumor cells engage an adaptive signaling pathway, the unfolded protein response (UPR) thus promoting the acquisition of malignant features. As such, glioblastoma multiforme (GBM), the most aggressive primary brain tumors, exhibit constitutive UPR signals to sustain growth. Herein, we showed that signaling elicited by one of the UPR sensors, IRE1, promotes GBM tumor invasion, angiogenesis and infiltration by macrophages. Hence, high IRE1 activity in tumors predicts worse outcome. We further dissect IRE1-dependent mechanisms that shape the brain tumor immune microenvironment towards myeloid cells. We identify an IRE1-dependent signaling pathway that directly controls the expression/release of proinflammatory chemokines (CXCL2, IL6, IL8) leading to tumor cell-mediated chemoattraction of neutrophils and macrophages. This pathway requires XBP1 non-conventional mRNA splicing and XBP1s-dependent expression of the E2 ubiquitin enzyme UBE2D3. The latter contributes to the degradation of the NFκB inhibitor IκB, leading to the up-regulation of proinflammatory chemokines. Our work identifies a novel IRE1/UBE2D3 proinflammatory signaling axis instrumental to pro-tumoral immune regulation of GBM.

Novel IRE1-dependent proinflammatory signaling controls tumor infiltration by myeloid cells