2. Academic Validation
  3. Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy

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

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. Michael.Reedijk@uhn.ca.
  • 8 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Michael.Reedijk@uhn.ca.
  • 9 Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Michael.Reedijk@uhn.ca.
  • # 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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