Metastases are the main cause of cancer-related deaths. Preventing hibernating cancer cells from awakening therefore represents an urgent, unmet medical need. To more successfully control cancer dormancy, we need to better establish just how these lurking cells lie inactive for long periods of time, as well as elucidate the cellular and molecular triggers that bring them out of their shady slumber.
Thanks to superb preclinical work led by Ana Luísa Correia and colleagues at the University of Basel, Switzerland, we might well be getting closer in achieving a deeper understanding of tumour cell dormancy and how to manipulate this potential therapeutic window for preventing metastatic disease. Recently reported in Nature the investigators evidence the pivotal role of natural killer (NK) cells in events that block the reawakening of these seeds of cancer dissemination (Nature. 2021 Jun;594(7864):566-571).
Specifically, the authors elegantly describe how cancer cell progression of breast cancer in the liver remained dormant or awoke to metastasize. Using mouse models and human tissue samples, they have identified the interaction between NK cells and hepatic stellate cells (HSCs) as a master switch of cancer dormancy. On the one hand, NKs secrete a molecular messenger, interferon gamma, which maintains cancer cell hibernation. On the other, when triggered by factors that might, suggest the authors, include chronic inflammation or infection, HSCs inhibit immune cells which leads to the subsequent awakening of cancer cells.
Based on their results, they suggest treatment approaches including adjuvant interleukin-15-based immunotherapy to boost the number of NK cells; interferon gamma therapy to sustain cancer cell dormancy; and inhibitors of the mechanism through which the activated HSCs disable NK cells – all of which require testing in the clinic. Findings point to the potential utility of immune-based therapies targeting natural KCs for the prevention of metastatic outgrowth in patients with sleeping cancer cells.
Whether this approach ultimately steps up or not, there is a long road ahead to translate these findings into therapeutic opportunities against cancer cell spread. But the race is now on to let sleeping dogs lie.