Correia, Ana Luísa and Guimaraes, Joao C. and Auf der Maur, Priska and De Silva, Duvini and Trefny, Marcel P. and Okamoto, Ryoko and Bruno, Sandro and Schmidt, Alexander and Mertz, Kirsten and Volkmann, Katrin and Terracciano, Luigi and Zippelius, Alfred and Vetter, Marcus and Kurzeder, Christian and Weber, Walter Paul and Bentires-Alj, Mohamed. (2021) Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature, 594 (7864). pp. 566-571.
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Official URL: https://edoc.unibas.ch/90861/
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Abstract
The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment; 1-3; . These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis; 4; that is often associated with a poor prognosis; 5; . Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.
Faculties and Departments: | 05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Proteomics (Schmidt) |
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UniBasel Contributors: | Schmidt, Alexander |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Macmillan |
ISSN: | 0028-0836 |
e-ISSN: | 1476-4687 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 08 Dec 2022 14:40 |
Deposited On: | 08 Dec 2022 14:40 |
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