GSE195439
Bulk RNAseq of control, XBP1-deficient or XBP1/IRE1-deficient cDC1s from subcutaneous B16- melanoma bearing mice
The unfolded protein response (UPR) sensor IRE1 and its target, the transcription factor XBP1s critically regulate the function of dendritic cell (DC) subtypes. However, the contribution of the IRE1/XBP1s axis in DCs to the antitumor immunity is not entirely understood. Here, using reporter mice we found that DCs, in particular type 1 conventional DCs (cDC1s), are major targets of IRE1 RNase activity in melanoma tumors. Deletion of XBP1s in CD11c+ cells resulted in augmented tumor growth, impaired effector T cell responses and decreased accumulation of TCF-1+CD8+ T cells with a precursor exhausted profile. Transcriptomic studies revealed that XBP1 deletion in tumor cDC1s induced regulated IRE1 dependent decay (RIDD) of mRNAs, which accounted for the dysregulated T cell immunity in melanoma. Thus, a strict regulatory circuit involving IRE1 RNase and XBP1s in DCs ensures optimal antitumor T cell immunity in melanoma models. Overall design: Bulk-RNAseq of intratumoral cDC1s isolated from B16 bearing control (wild-type) mice or conditional deficient mice for XBP1 or XBP1/IRE1 in CD11c+ cells. Each data point comes from 2-4 pooled mice with the same genotype and replicates correspond to independent pools.