Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy

Ana Luísa Correia (), Joao C. Guimaraes, Priska Auf der Maur, Duvini De Silva, Marcel P. Trefny, Ryoko Okamoto, Sandro Bruno, Alexander Schmidt, Kirsten Mertz, Katrin Volkmann, Luigi Terracciano, Alfred Zippelius, Marcus Vetter, Christian Kurzeder, Walter Paul Weber and Mohamed Bentires-Alj ()
Additional contact information
Ana Luísa Correia: University of Basel
Joao C. Guimaraes: Biozentrum, University of Basel
Priska Auf der Maur: University of Basel
Duvini De Silva: University of Basel
Marcel P. Trefny: University of Basel
Ryoko Okamoto: University of Basel
Sandro Bruno: Friedrich Miescher Institute for Biomedical Research
Alexander Schmidt: University of Basel
Kirsten Mertz: Cantonal Hospital Basel-Land
Katrin Volkmann: University of Basel
Luigi Terracciano: University Hospital Basel
Alfred Zippelius: University of Basel
Marcus Vetter: University Hospital Basel
Christian Kurzeder: University Hospital Basel
Walter Paul Weber: University Hospital Basel
Mohamed Bentires-Alj: University of Basel

Nature, 2021, vol. 594, issue 7864, 566-571

Abstract: Abstract The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1–3. 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 metastasis4 that is often associated with a poor prognosis5. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03614-z

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