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Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer
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 c...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829901/ https://www.ncbi.nlm.nih.gov/pubmed/36624093 http://dx.doi.org/10.1038/s41467-022-35584-9 |
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author | Crowley, Michael J. P. Bhinder, Bhavneet Markowitz, Geoffrey J. Martin, Mitchell Verma, Akanksha Sandoval, Tito A. Chae, Chang-Suk Yomtoubian, Shira Hu, Yang Chopra, Sahil Tavarez, Diamile A. Giovanelli, Paolo Gao, Dingcheng McGraw, Timothy E. Altorki, Nasser K. Elemento, Olivier Cubillos-Ruiz, Juan R. Mittal, Vivek |
author_facet | Crowley, Michael J. P. Bhinder, Bhavneet Markowitz, Geoffrey J. Martin, Mitchell Verma, Akanksha Sandoval, Tito A. Chae, Chang-Suk Yomtoubian, Shira Hu, Yang Chopra, Sahil Tavarez, Diamile A. Giovanelli, Paolo Gao, Dingcheng McGraw, Timothy E. Altorki, Nasser K. Elemento, Olivier Cubillos-Ruiz, Juan R. Mittal, Vivek |
author_sort | Crowley, Michael J. P. |
collection | PubMed |
description | 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 E(2). Accordingly, restoring mPGES-1 expression in IRE1α(KO) 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. |
format | Online Article Text |
id | pubmed-9829901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98299012023-01-11 Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer Crowley, Michael J. P. Bhinder, Bhavneet Markowitz, Geoffrey J. Martin, Mitchell Verma, Akanksha Sandoval, Tito A. Chae, Chang-Suk Yomtoubian, Shira Hu, Yang Chopra, Sahil Tavarez, Diamile A. Giovanelli, Paolo Gao, Dingcheng McGraw, Timothy E. Altorki, Nasser K. Elemento, Olivier Cubillos-Ruiz, Juan R. Mittal, Vivek Nat Commun Article 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 E(2). Accordingly, restoring mPGES-1 expression in IRE1α(KO) 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. Nature Publishing Group UK 2023-01-09 /pmc/articles/PMC9829901/ /pubmed/36624093 http://dx.doi.org/10.1038/s41467-022-35584-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Crowley, Michael J. P. Bhinder, Bhavneet Markowitz, Geoffrey J. Martin, Mitchell Verma, Akanksha Sandoval, Tito A. Chae, Chang-Suk Yomtoubian, Shira Hu, Yang Chopra, Sahil Tavarez, Diamile A. Giovanelli, Paolo Gao, Dingcheng McGraw, Timothy E. Altorki, Nasser K. Elemento, Olivier Cubillos-Ruiz, Juan R. Mittal, Vivek Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer |
title | Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer |
title_full | Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer |
title_fullStr | Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer |
title_full_unstemmed | Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer |
title_short | Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer |
title_sort | tumor-intrinsic ire1α signaling controls protective immunity in lung cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829901/ https://www.ncbi.nlm.nih.gov/pubmed/36624093 http://dx.doi.org/10.1038/s41467-022-35584-9 |
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