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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-022-35584-9

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