Hepatic stellate cells suppress NK cell sustained breast cancer dormancy

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment. 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 singular therapeutic window to prevent metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of dormant DTC reservoirs is imperative. Here we reveal tissue-specific microenvironments that restrain or allow progression of breast cancer in the liver, a frequent site of metastasis and often associated with patients' cause of death. Using mouse models, we show that the dormant milieu features a selective rise in natural killer (NK) cells. Adjuvant interleukin-15-based immunotherapy ensures an abundant NK cell pool that sustains dormancy through IFN-gama signalling, preventing hepatic metastases and prolonging survival. Exit from dormancy follows a dramatic contraction of the NK cell compartment and concurrent accumulation of activated stellate cells. Our proteomics studies on liver co-cultures implicate the chemokine CXCL12 secreted by activated stellate cells in inducing NK cell quiescence via its cognate receptor CXCR4. Expression of CXCL12 and activated stellate cell abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and activated stellate cells as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing DTC outgrowth and metastasis.