STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion.
Richard Moriggl contributed to a recent report in Cancer Discovery about STAT5 signaling. It is known that natural killer (NK) cells are tightly regulated by the JAK-STAT signaling pathway and cannot survive in the absence of STAT5. The authors now report that STAT5-deficient NK cells can be rescued by overexpression of BCL2. Experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-deficient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The contribution of VEGFA produced by NK cells was verified by conditional knockout of VEGFA in NK cells. While STAT5 normally represses the transcription of VEGFA in NK cells these findings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell-mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis.
The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK-STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK-STAT5 has the potential to promote tumor growth by enhancing NK-cell-mediated angiogenesis.
We congratulate Richard Moriggl and his colleagues to this successful collaboration.