Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer

Michael J.P. Crowley, Bhavneet Bhinder, Geoffrey J. Markowitz, Mitchell Martin, Akanksha Verma, Tito A. Sandoval, Chang Suk Chae, Shira Yomtoubian, Yang Hu, Sahil Chopra, Diamile A. Tavarez, Paolo Giovanelli, Dingcheng Gao, Timothy E. McGraw, Nasser K. Altorki, Olivier Elemento, Juan R. Cubillos-Ruiz, Vivek Mittal

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


IRE1α-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 IRE1α 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 IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E2. Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

Original languageEnglish (US)
Article number120
Pages (from-to)120
JournalNature Communications
Issue number1
StatePublished - Jan 9 2023


  • Animals
  • Humans
  • Mice
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Endoribonucleases/genetics
  • Lung Neoplasms/genetics
  • Protein Serine-Threonine Kinases/genetics
  • Signal Transduction
  • X-Box Binding Protein 1/genetics

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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