Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models.
Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models.
复制标题
DOI：
10.1038/ncomms12258
复制
发表时间：
2016-07-13
影响因子：
16.6
通讯作者：
Hynes NE
中科院分区：
文献类型：
--
作者：
Bottos A;Gotthardt D;Gill JW;Gattelli A;Frei A;Tzankov A;Sexl V;Wodnar-Filipowicz A;Hynes NE
JAK/STAT通路因其频繁激活而成为乳腺癌治疗的一个有吸引力的靶点，评估JAK抑制剂(JAK)治疗晚期乳腺癌的临床试验仍在进行中。使用患者活检和乳腺癌的临床前模型，我们证明了JAK/STAT通路在转移中是活跃的。出乎意料的是，在乳腺癌转移的实验和原位模型中，用Jaki阻断该通路会增加转移负担。我们证明，这种转移效应是由于Jaki的免疫抑制活性，继而损害了NK细胞介导的抗肿瘤免疫。此外，我们还发现IL-15的免疫刺激作用克服了Jaki对转移形成的促进作用。我们的发现强调了评估靶向治疗对肿瘤环境的影响的重要性。Jaki对NK细胞的影响以及免疫刺激剂克服肿瘤免疫监视功能减弱的潜在价值，值得在乳腺癌的临床应用中加以考虑。JAK抑制剂目前正在接受晚期乳腺癌的临床试验评估。在这里，作者表明，JAK通路抑制通过削弱NK抗肿瘤活性来增加乳腺癌小鼠模型的转移，这些副作用可以通过添加IL-15来克服。
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 inhibitors are currently undergoing evaluation in clinical trials for advanced breast cancer. Here, the authors show that JAK pathway inhibition increases metastasis in mouse models of breast cancer by impairing NK anti-tumour activity and that these side effects can be overcome by addition of IL-15.