IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer

doi:10.1016/j.cell.2024.09.032

. 2024 Oct 14:S0092-8674(24)01090-0.

doi: 10.1016/j.cell.2024.09.032. Online ahead of print.

IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer

Longyong Xu¹, Fanglue Peng², Qin Luo¹, Yao Ding¹, Fei Yuan³, Liting Zheng⁴, Wei He⁵, Sophie S Zhang⁶, Xin Fu⁷, Jin Liu⁷, Ayse Sena Mutlu⁴, Shuyue Wang⁵, Ralf Bernd Nehring⁴, Xingyu Li⁸, Qianzi Tang⁸, Catherine Li¹, Xiangdong Lv¹, Lacey E Dobrolecki², Weijie Zhang², Dong Han², Na Zhao², Eric Jaehnig², Jingyi Wang², Weiche Wu¹, Davis A Graham², Yumei Li⁴, Rui Chen⁴, Weiyi Peng⁹, Yiwen Chen¹⁰, Andre Catic², Zhibin Zhang¹¹, Bing Zhang², Anthony M Mustoe⁴, Albert C Koong¹², George Miles², Michael T Lewis², Meng C Wang¹³, Susan M Rosenberg⁴, Bert W O'Malley², Thomas F Westbrook⁴, Han Xu⁵, Xiang H-F Zhang², C Kent Osborne², Jin Billy Li¹⁴, Matthew J Ellis², Mothaffar F Rimawi², Jeffrey M Rosen², Xi Chen¹⁵

Affiliations

¹ Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dun L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Therapeutic Innovation Center (THINC), and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Chemistry, Rice University, Houston, TX 77005, USA.
⁷ Department of Pathology, Xijing Hospital, Xi'an, Shaanxi 710032, China.
⁸ College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China.
⁹ Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
¹⁰ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ HHMI Janelia Research Campus, Ashburn, VA 20147, USA.
¹⁴ Department of Genetics, Stanford University, Stanford, CA 94305, USA.
¹⁵ Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dun L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: xchen23@mdanderson.org.

PMID: 39419025
DOI: 10.1016/j.cell.2024.09.032

IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer

Longyong Xu et al. Cell. 2024.

. 2024 Oct 14:S0092-8674(24)01090-0.

doi: 10.1016/j.cell.2024.09.032. Online ahead of print.

Authors

Affiliations

¹ Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dun L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Therapeutic Innovation Center (THINC), and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Chemistry, Rice University, Houston, TX 77005, USA.
⁷ Department of Pathology, Xijing Hospital, Xi'an, Shaanxi 710032, China.
⁸ College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China.
⁹ Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
¹⁰ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ HHMI Janelia Research Campus, Ashburn, VA 20147, USA.
¹⁴ Department of Genetics, Stanford University, Stanford, CA 94305, USA.
¹⁵ Department of Experimental Therapeutics, James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dun L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: xchen23@mdanderson.org.

PMID: 39419025
DOI: 10.1016/j.cell.2024.09.032

Abstract

Chemotherapy is often combined with immune checkpoint inhibitor (ICIs) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced double-stranded RNA (dsRNA) through regulated IRE1-dependent decay (RIDD) to prevent NLRP3 inflammasome-dependent pyroptosis. Inhibition of IRE1α in Trp53^-/- TNBC allows taxane to induce extensive dsRNAs that are sensed by ZBP1, which in turn activates NLRP3-GSDMD-mediated pyroptosis. Consequently, IRE1α RNase inhibitor plus taxane converts PD-L1-negative, ICI-unresponsive TNBC tumors into PD-L1^high immunogenic tumors that are hyper-sensitive to ICI. We reveal IRE1α as a cancer cell defense mechanism that prevents taxane-induced danger signal accumulation and pyroptotic cell death.

Keywords: ER stress; IRE1α; PD-L1-negative breast cancer; dsRNA; pyroptosis.

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Conflict of interest statement

Declaration of interests M.F.R. receives research funding from Pfizer and Genentech and consulting fees from Novartis, Seagen, Macrogenics, and AstraZeneca. M.F.R. is the PI of clinical trial NCT03950570. X.C. reports previous research funding from Fosun Pharma. M.J.E. holds patents and receives income from Veracyte on the PAM50-based products, Prosigna.

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IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer

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IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer

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