Nature Communications (Oct 2024)

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

  • Weiyue Zheng,
  • Wanda Marini,
  • Kiichi Murakami,
  • Valentin Sotov,
  • Marcus Butler,
  • Chiara Gorrini,
  • Pamela S. Ohashi,
  • Michael Reedijk

DOI
https://doi.org/10.1038/s41467-024-52553-6
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 13

Abstract

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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.