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The protumorigenic potential of FTY720 by promoting extramedullary hematopoiesis and MDSC accumulation

Oncogene volume 36, pages 3760–3771 (2017)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from the National Key Basic Research Program of China (2015CB553704, 2013CB530506), the National Natural Science Foundation of China (81672803, 81472647, 81272320), Beijing Natural Science Foundation (7132151), Service Industry Scientific Research of National Health and Family Planning Commission of China (2015SQ00192).

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Author notes

  1. Y Li, T Zhou, Y Wang and C Ning: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Institute of Basic Medical Sciences, Beijing, People’s Republic of China

    Y Li, T Zhou, Y Wang, C Ning, Z Lv, G Han, R Wang, H Xiao, C Hou, B Shen, J Feng, Y Li & G Chen

  2. Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, People’s Republic of China

    Y Li & Y Ma

  3. Department of Internal Medicine, People’s Hospital of Luanchuan County, Luoyang, People’s Republic of China

    Y Li

  4. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People’s Republic of China

    Y Li, T Zhou, G Han, R Wang, H Xiao, C Hou, B Shen, J Feng, Y Li & G Chen

  5. Department of Hematology and Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China

    Y Wang

  6. Department of Oncology, the 161st Hospital of the PLA, Wuhan, People’s Republic of China

    C Ning

  7. School of Chemistry, University of New South Wales, Sydney, NSW, Australia

    J C Morris & E N Taylor

  8. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    R Guo

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Li, Y., Zhou, T., Wang, Y. et al. The protumorigenic potential of FTY720 by promoting extramedullary hematopoiesis and MDSC accumulation. Oncogene 36, 3760–3771 (2017). https://doi.org/10.1038/onc.2017.2

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