Zhu Fang, McCaw Lindsay, Spaner David E, Gorczynski Reginald M
Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Transplant Research Division, Toronto General Hospital, Toronto, Canada.
Biology Platform, Sunnybrook Research Institute, Toronto, Canada.
Leuk Res. 2018 Mar;66:28-38. doi: 10.1016/j.leukres.2018.01.006. Epub 2018 Jan 17.
The tumor microenvironment (TME) is critical to the longevity of tumor B cells in chronic lymphocytic leukemia (CLL). Bone marrow mesenchymal stem cells (BMMSCs) and the cytokines they produce including IL-6 are important components of the TME in CLL. We found BMMSCs supported the survival of CLL cells in vitro through an IL-6 dependent mechanism. IL-17 which induces IL-6 generation in a variety of cells increased production of IL-6 both in CLL cells and BMMSCs in vitro. In a xenograft CLL mouse model, BMMSCs and the culture supernatant of BMMSCs increased engraftment of CLL cells through an IL-6 mediated mechanism with human recombinant IL-6 showing similar effects in vivo. Human recombinant IL-17 treatment also increased CLL engraftment in mice through an IL-6 mediated mechanism. Plasma of CLL patients showed elevated levels of both IL-6 and IL-17 by ELISA compared with healthy controls, with levels of IL-6 linearly correlated with IL-17 levels. CLL patients requiring fludarabine based chemotherapy expressed higher levels of IL-6 and IL-17, while CLL patients with the lowest levels of IgA/IgM had higher levels of IL-6, but not IL-17. These data imply an important role for the IL-17/IL-6 axis in CLL which could be therapeutic targets.
肿瘤微环境（TME）对于慢性淋巴细胞白血病（CLL）中肿瘤B细胞的存活至关重要。骨髓间充质干细胞（BMMSCs）及其产生的细胞因子（包括IL-6）是CLL中TME的重要组成部分。我们发现BMMSCs在体外通过依赖IL-6的机制支持CLL细胞的存活。IL-17可在多种细胞中诱导IL-6生成，在体外可增加CLL细胞和BMMSCs中IL-6的产生。在异种移植CLL小鼠模型中，BMMSCs和BMMSCs的培养上清液通过IL-6介导的机制增加CLL细胞的植入，人重组IL-6在体内显示出类似的作用。人重组IL-17治疗也通过IL-6介导的机制增加小鼠中CLL的植入。通过ELISA检测，CLL患者血浆中IL-6和IL-17水平均高于健康对照，IL-6水平与IL-17水平呈线性相关。需要基于氟达拉滨化疗的CLL患者表达较高水平的IL-6和IL-17，而IgA/IgM水平最低的CLL患者IL-6水平较高，但IL-17水平不高。这些数据表明IL-17/IL-6轴在CLL中起重要作用，可能成为治疗靶点。
