@article{68eadc6132854e189c0c2d5ba5293548,
title = "Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer",
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.",
keywords = "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",
author = "Crowley, {Michael J.P.} and Bhavneet Bhinder and Markowitz, {Geoffrey J.} and Mitchell Martin and Akanksha Verma and Sandoval, {Tito A.} and Chae, {Chang Suk} and Shira Yomtoubian and Yang Hu and Sahil Chopra and Tavarez, {Diamile A.} and Paolo Giovanelli and Dingcheng Gao and McGraw, {Timothy E.} and Altorki, {Nasser K.} and Olivier Elemento and Cubillos-Ruiz, {Juan R.} and Vivek Mittal",
note = "Funding Information: We thank Dr. Jenny Xiang of the Genomics Resources Core Facility, Jason McCormick of the Flow Cytometry Core Facility, and Abu Nasar for clinical data support. This work was supported in part by the US Department of Defense LCRP award LC180486 (V.M. and J.R.C.-R.). M.J.P.C. was supported by the F31 National Institutes of Health predoctoral fellowship CA217032-01. J.R.C.-R. was also supported by the National Institutes of Health (R01NS114653 and R21CA248106), the US Department of Defense (W81XWH2110357, W81XWH1610438, and W81XWH2010191), Stand Up to Cancer (SU2C-AACR-IRG-03-16 and SU2C-AACR-PS24), the Pershing Square Sohn Cancer Research Alliance, the Mark Foundation for Cancer Research ASPIRE Award, and the Wade F. B. Thompson/Cancer Research Institute CLIP grant. This work was also supported by funds from The Neuberger Berman Foundation Lung Cancer Research Center; a generous gift from Jay and Vicky Furman; and generous funds donated by patients in the Division of Thoracic Surgery to N.K.A. The funding organizations played no role in experimental design, data analysis, or manuscript preparation. Funding Information: J.R.C.-R. is a scientific consultant for NextRNA Therapeutics, Inc. and Autoimmunity Biologic Solutions, Inc, and holds patents on IRE1α modulation for the treatment of disease. O.E. is supported by Janssen, J&J, Astra-Zeneca, Volastra, and Eli Lilly research grants. He is a scientific advisor and equity holder in Freenome, Owkin, Volastra Therapeutics, and One Three Biotech and a paid scientific advisor to Champions Oncology and Pionyr Immunotherapeutics. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = jan,
day = "9",
doi = "10.1038/s41467-022-35584-9",
language = "English (US)",
volume = "14",
pages = "120",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}