IRE1-UBE2D3 signaling controls the recruitment of myeloid cells to glioblastoma

Many intrinsic and environmental stresses trigger the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. This condition has been observed in various human diseases, including cancer. As such, glioblastoma multiforme (GBM), the most aggressive and lethal primary brain tumor, was reported to present features of ER stress and to depend on ER stress signaling to sustain growth. Tumor cells can also use unfolded protein response (UPR) signaling to acquire malignant features thereby promoting tumor progression. IRE1 is a central mediator of the UPR, whose RNase activity leads to the non-conventional splicing of XBP1 mRNA and RNA degradation through Regulated IRE1 dependent decay (RIDD). We recently showed that IRE1 activity in GBM promotes tumor invasion, angiogenesis and infiltration by macrophages. Hence, high tumor IRE1 activity predicted worse outcome in vivo. Herein, we further characterize the IRE1-dependent signaling mechanism that shapes the brain tumor immune microenvironment, in particular towards myeloid cells. The latter phenomenon is mediated in part by IRE1-dependent regulation of CXCL2, IL6 and IL8 expression. We further found that IRE1 through the XBP1s transcriptional activity induces the expression of E2 ubiquitin enzyme UBE2D3, which in turn promotes inflammation. We show that UBE2D3 triggers the recruitment of myeloid cells to tumors in vitro and in vivo by targeting the NFKB signaling inhibitor, IKB leading to the up-regulation of pro-inflammatory chemokines expression. Our work identifies a novel IRE1/UBE2D3 signaling axis that plays an instrumental role in the immune regulation of glioblastoma.