Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy.
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Embargo End Date
ICR Authors
Authors
Zheng, W
Marini, W
Murakami, K
Sotov, V
Butler, M
Gorrini, C
Ohashi, PS
Reedijk, M
Marini, W
Murakami, K
Sotov, V
Butler, M
Gorrini, C
Ohashi, PS
Reedijk, M
Document Type
Journal Article
Date
2024-10-01
Date Accepted
2024-09-12
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.
Citation
Nature Communications, 2024, 15 (1), pp. 8514 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Paediatric Tumour Biology