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 and Michael Reedijk ()
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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
Chiara Gorrini: University Health Network
Pamela S. Ohashi: University Health Network
Michael Reedijk: University Health Network

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52553-6

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