Tumor-intrinsic IRE1 signaling controls protective immunity in lung cancer

IRE1 alpha-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1 alpha in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1 alpha activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E-2. Accordingly, restoring mPGES-1 expression in IRE1 alpha(KO) cancer cells rescues normal tumor progression. We have developed an IRE1 alpha gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1 alpha activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.