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

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.

Metadata

Item Type:	Article
Authors/Creators:	Zheng, W. https://orcid.org/0009-0000-6485-9488 Marini, W. Murakami, K. Sotov, V. Butler, M. https://orcid.org/0000-0002-9840-7057 Gorrini, C. https://orcid.org/0000-0002-5239-6671 Ohashi, P.S. Reedijk, M. https://orcid.org/0000-0002-4305-723X
Copyright, Publisher and Additional Information:	© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	CD8-Positive T-Lymphocytes; Cell Line, Tumor; Animals; Humans; Mice; Caspase 1; Estrogen Receptor alpha; Immunotherapy; Gene Expression Regulation, Neoplastic; Female; Proto-Oncogene Protein c-ets-1; Interleukin-1beta; Tumor Microenvironment; Triple Negative Breast Neoplasms; Immune Checkpoint Inhibitors; Tumor-Associated Macrophages
Dates:	Published: 1 October 2024 Published (online): 1 October 2024 Accepted: 12 September 2024
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	14 Oct 2024 12:30
Last Modified:	14 Oct 2024 12:30
Published Version:	https://doi.org/10.1038/s41467-024-52553-6
Status:	Published
Publisher:	Springer
Identification Number:	10.1038/s41467-024-52553-6
Related URLs:	PubMed URL Dataset Dataset Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:218291

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

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

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