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

  • Nat Commun. 2024 Oct 1;15(1):8514. doi: 10.1038/s41467-024-52553-6.
Weiyue Zheng  #  1 ,  Wanda Marini  #  1 ,  Kiichi Murakami  1 ,  Valentin Sotov  1 ,  Marcus Butler  1  2  3 ,  Chiara Gorrini  1  4 ,  Pamela S Ohashi  1  5  6 ,  Michael Reedijk  7  8  9
Affiliations
  • 1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 2. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 3. Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, ON, Canada.
  • 4. School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
  • 5. Department of Immunology, University of Toronto, Toronto, ON, Canada.
  • 6. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 7. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
  • 8. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [email protected].
  • 9. Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 39353903 DOI: 10.1038/s41467-024-52553-6
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.

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