Activation of IRE1 RNase in dendritic cells curtails antitumor adaptive immunity in melanoma.

Abstract

Abstract The unfolded protein response (UPR) sensor IRE1 (inositol-requiring enzyme 1 alpha) and its target, the transcription factor XBP1s (X-box binding protein 1, spliced) critically regulates the function of dendritic cell (DC) subtypes. However, the contribution of the IRE1/XBP1s axis in DC subsets to the initiation of antitumor immunity is not entirely understood. In this work, 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 DCs resulted in augmented tumor growth, impaired effector T cell responses and marked accumulation of TIM-3+CD8+ T cells with a terminal exhausted profile. Transcriptomic studies further revealed that XBP1s deletion in tumor cDC1s induced the loss of major proteostasis core genes and elicited mRNA degradation via regulated IRE1-dependent decay (RIDD), which accounted for the dysregulated T cell immunity in melanoma. Thus, our work demonstrates that a strict regulatory circuit involving IRE1 RNase and XBP1s in DCs ensures optimal antitumor T cell immunity in melanoma models. Supported by HHMI international research scholar grant # 55008744 FONDECYT (National Fund for Scientific and Technological Development) #1200793 CONICYT-PFCHA/DoctoradoNacional/2017-21170366