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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
    • Publication Information:
      Publication: Cambridge, Ma : Cell Press
      Original Publication: Cambridge, MIT Press.
    • Subject Terms:
      Triple Negative Breast Neoplasms*/drug therapy ; Triple Negative Breast Neoplasms*/pathology ; Triple Negative Breast Neoplasms*/metabolism ; Pyroptosis*/drug effects ; Endoribonucleases*/metabolism ; Taxoids*/pharmacology ; Taxoids*/therapeutic use ; RNA, Double-Stranded*/metabolism ; Protein Serine-Threonine Kinases*/metabolism; Humans ; Female ; Animals ; Cell Line, Tumor ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Bridged-Ring Compounds/pharmacology ; Inflammasomes/metabolism ; B7-H1 Antigen/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Immune Checkpoint Inhibitors/pharmacology
    • 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.
      Competing Interests: 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.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
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    • Grant Information:
      R01 CA250905 United States CA NCI NIH HHS; R37 CA228304 United States CA NCI NIH HHS; R01 HL146642 United States HL NHLBI NIH HHS; DP1 AG072751 United States AG NIA NIH HHS; R01 DK115454 United States DK NIDDK NIH HHS; R01 CA270240 United States CA NCI NIH HHS; P50 CA186784 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: ER stress; IRE1α; PD-L1-negative breast cancer; dsRNA; pyroptosis
    • Accession Number:
      EC 3.1.- (Endoribonucleases)
      0 (Taxoids)
      1605-68-1 (taxane)
      0 (RNA, Double-Stranded)
      EC 2.7.11.1 (ERN1 protein, human)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      0 (NLR Family, Pyrin Domain-Containing 3 Protein)
      0 (Bridged-Ring Compounds)
      0 (Inflammasomes)
      0 (B7-H1 Antigen)
      0 (Immune Checkpoint Inhibitors)
    • Publication Date:
      Date Created: 20241017 Date Completed: 20241213 Latest Revision: 20241215
    • Publication Date:
      20241215
    • Accession Number:
      PMC11645245
    • Accession Number:
      10.1016/j.cell.2024.09.032
    • Accession Number:
      39419025