Abstract
The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Using patient biopsies and preclinical models of breast cancer, we demonstrate that the JAK/STAT pathway is active in metastasis. Unexpectedly, blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. Furthermore, we show that immunostimulation with IL-15 overcomes the enhancing effect of JAKi on metastasis formation. Our findings highlight the importance of evaluating the effect of targeted therapy on the tumour environment. The impact of JAKi on NK cells and the potential value of immunostimulators to overcome the weakened tumour immunosurveillance, are worthwhile considering in the clinical setting of breast cancer.
Highlights
The janus kinases (JAK)/signal transducer and activator of transcription (STAT) pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing
We examined the level of tyrosine phosphorylated (p)STAT3 and pSTAT5 in clinical samples from primary breast cancers and paired bone metastases (Supplementary Table 1). 93% and 57% of primary tumours were positive for pSTAT3 and pSTAT5, respectively
In searching for approaches to overcome the immunosuppressive effect of JAKi, we investigated whether enhancing NK-cell function through IL-15 stimulation, would reduce metastasis in the context of JAK2 inhibition
Summary
The JAK/STAT pathway is an attractive target for breast cancer therapy due to its frequent activation, and clinical trials evaluating JAK inhibitors (JAKi) in advanced breast cancer are ongoing. Blocking the pathway with JAKi enhances the metastatic burden in experimental and orthotopic models of breast cancer metastasis. We demonstrate that this prometastatic effect is due to the immunosuppressive activity of JAKi with ensuing impairment of NK-cell-mediated anti-tumour immunity. With the rationale in mind that the JAK/STAT pathway controls key aspects of the innate tumour immunity, it becomes very important to understand how metastasis formation is influenced by treatment with JAKi. The results we present here show that inhibition of the JAK pathway, despite blocking STAT activation in tumour cells, enhances metastatic burden in preclinical models of breast cancer by decreasing NK-cell-mediated antitumour immunity
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