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Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy

Author

Listed:
  • Weiyue Zheng

    (University Health Network)

  • Wanda Marini

    (University Health Network)

  • Kiichi Murakami

    (University Health Network)

  • Valentin Sotov

    (University Health Network)

  • Marcus Butler

    (University Health Network
    University Health Network
    University of Toronto)

  • Chiara Gorrini

    (University Health Network
    University of Leeds)

  • Pamela S. Ohashi

    (University Health Network
    University of Toronto
    University of Toronto)

  • Michael Reedijk

    (University Health Network
    University of Toronto
    University Health Network)

Abstract

Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1β in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization.

Suggested Citation

  • Weiyue Zheng & Wanda Marini & Kiichi Murakami & Valentin Sotov & Marcus Butler & Chiara Gorrini & Pamela S. Ohashi & Michael Reedijk, 2024. "Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52553-6
    DOI: 10.1038/s41467-024-52553-6
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    1. Nina Linde & Maria Casanova-Acebes & Maria Soledad Sosa & Arthur Mortha & Adeeb Rahman & Eduardo Farias & Kathryn Harper & Ethan Tardio & Ivan Reyes Torres & Joan Jones & John Condeelis & Miriam Merad, 2018. "Macrophages orchestrate breast cancer early dissemination and metastasis," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Xiao Qian Wang & Esther Danenberg & Chiun-Sheng Huang & Daniel Egle & Maurizio Callari & Begoña Bermejo & Matteo Dugo & Claudio Zamagni & Marc Thill & Anton Anton & Stefania Zambelli & Stefania Russo , 2023. "Spatial predictors of immunotherapy response in triple-negative breast cancer," Nature, Nature, vol. 621(7980), pages 868-876, September.
    3. Dora Hammerl & John W. M. Martens & Mieke Timmermans & Marcel Smid & Anita M. Trapman-Jansen & Renée Foekens & Olga I. Isaeva & Leonie Voorwerk & Hayri E. Balcioglu & Rebecca Wijers & Iris Nederlof & , 2021. "Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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