Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, People's Republic of China.
Oncogene. 2017 Jun 29;36(26):3760-3771. doi: 10.1038/onc.2017.2. Epub 2017 Feb 20.
FTY720 (also called fingolimod) is recognized as an immunosuppressant and has been approved by the Food and Drug Administration to treat refractory multiple sclerosis. However, long-term administration of FTY720 potentially increases the risk for cancer in recipients. The underlying mechanisms remain poorly understood. Herein, we provided evidence that FTY720 administration potentiated tumor growth. Mechanistically, FTY720 enhanced extramedullary hematopoiesis and massive accumulation of myeloid-derived suppressor cells (MDSCs), which actively suppressed antitumor immune responses. Granulocyte-macrophage colony-stimulating factor (GM-CSF), mainly produced by MDSCs, was identified as a key factor to mediate these effects of FTY720 in tumor microenvironment. Furthermore, we showed that FTY720 triggers MDSCs to release GM-CSF via S1P receptor 3 (S1pr3) through Rho kinase and extracellular signal-regulated kinase-dependent pathway. Thus, our findings provide mechanistic explanation for the protumorigenic potentials of FTY720 and suggest that targeting S1pr3 simultaneously may be beneficial for the patients receiving FTY720 treatment.
FTY720（也称为 fingolimod）被认为是一种免疫抑制剂，已被美国食品和药物管理局批准用于治疗难治性多发性硬化症。然而，长期使用 FTY720 可能会增加接受者患癌症的风险。其潜在的机制仍知之甚少。在此，我们提供了 FTY720 给药会增强肿瘤生长的证据。从机制上讲，FTY720 增强了骨髓外造血和大量髓系来源的抑制细胞（MDSC）的积累，这些细胞积极抑制了抗肿瘤免疫反应。粒细胞-巨噬细胞集落刺激因子（GM-CSF）主要由 MDSC 产生，被鉴定为介导 FTY720 在肿瘤微环境中这些作用的关键因素。此外，我们表明 FTY720 通过 Rho 激酶和细胞外信号调节激酶依赖性途径通过 S1P 受体 3（S1pr3）触发 MDSC 释放 GM-CSF。因此，我们的研究结果为 FTY720 的促肿瘤潜能提供了机制解释，并表明同时靶向 S1pr3 可能有益于接受 FTY720 治疗的患者。
