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

Affiliations

• 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
• Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
• 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
• Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
• Department of Chemistry, Rice University, Houston, TX 77005, USA
• Department of Pathology, Xijing Hospital, Xi'an, Shaanxi 710032, China
• Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
• College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
• Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
• Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
• Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
• HHMI Janelia Research Campus, Ashburn, VA 20147, USA
• Department of Genetics, Stanford University, Stanford, CA 94305, USA

PMID:    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-L1high 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.

化疗通常与免疫检查点抑制剂（ICIs）联合使用，以增强免疫治疗的效果。尽管这种联合疗法已经在多种癌症中获批，许多免疫冷肿瘤仍然没有响应。决定化疗免疫原性的机制尚不明确。本研究发现，内质网应激传感器IRE1α是限制紫杉烷类化疗免疫刺激效果的关键检查点，并阻止了免疫冷三阴性乳腺癌（TNBC）的先天免疫识别。IRE1α核糖核酸酶通过调控的IRE1依赖性降解（RIDD）抑制紫杉烷诱导的双链RNA（dsRNA），从而防止NLRP3炎性小体依赖的细胞焦亡。在Trp53−/− TNBC中抑制IRE1α后，紫杉烷能够诱导大量双链RNA，这些RNA由ZBP1感知，并进一步激活NLRP3-GSDMD介导的细胞焦亡。因此，IRE1α核糖核酸酶抑制剂与紫杉烷联合使用，可将PD-L1阴性、对ICIs无反应的TNBC肿瘤转化为PD-L1高表达的免疫原性肿瘤，使其对ICIs高度敏感。我们揭示了IRE1α作为癌细胞防御机制，能够阻止紫杉烷诱导的危险信号积累和细胞焦亡。