Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, Austria.
Nat Commun. 2016 Jul 13;7:12258. doi: 10.1038/ncomms12258.
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.
JAK/STAT 通路是乳腺癌治疗的一个有吸引力的靶点，因为它经常被激活，目前正在进行评估 JAK 抑制剂（JAKi）在晚期乳腺癌中的临床试验。我们使用患者的活检和乳腺癌的临床前模型证明，JAK/STAT 通路在转移中是活跃的。出乎意料的是，用 JAKi 阻断该通路会增强乳腺癌转移的实验和原位模型中的转移负担。我们证明这种促转移作用是由于 JAKi 的免疫抑制活性，从而导致 NK 细胞介导的抗肿瘤免疫受损。此外，我们表明，用 IL-15 进行免疫刺激可以克服 JAKi 对转移形成的增强作用。我们的研究结果强调了评估靶向治疗对肿瘤环境影响的重要性。在乳腺癌的临床环境中，JAKi 对 NK 细胞的影响以及免疫刺激剂克服肿瘤免疫监视减弱的潜在价值值得考虑。
