Tumor-intrinsic IRE1a signaling controls protective immunity in lung cancer.

The IRE1a-XBP1 arm of the unfolded protein response (UPR) has emerged as a central orchestrator of malignant progression and immunosuppression in various cancer types. Yet the role of this pathway in non-small cell lung cancer (NSCLC) has remained largely unexplored. Using an RNA-seq based computational XBP1s detection method applied to TCGA datasets, we uncovered that expression of the IRE1a-generated XBP1s mRNA isoform predicts poor survival in NSCLC patients. Ablation of IRE1a in malignant cells delayed tumor progression and extended survival in an XBP1-dependent fashion in mouse models of NSCLC. This protective effect was accompanied by marked alterations in both lymphoid and myeloid intratumoral cell subsets that elicited durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1a activation sustained mPGES-1 expression, enabling production of the immunosuppressive lipid mediator PGE2 in the tumor microenvironment (TME). Accordingly, restoring mPGES-1 expression in IRE1aKO cancer cells rescued normal tumor progression. By identifying the dominant transcriptional networks controlled by IRE1a in mouse lung tumors, we further developed a new gene signature that predicted immune cell infiltration and overall survival in human NSCLC. Hence, our study unveils a key immunoregulatory role for cancer cell-intrinsic IRE1a activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC. Overall design: Examination of IRE1a WT and KO murine NSCLC cell line (KRAS;p53), sorted from lung lesions at two time points (day 10 and day 14).