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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Fingolimod Hydrochloride / adverse effects*
  • Fingolimod Hydrochloride / pharmacology
  • Hematopoiesis, Extramedullary / drug effects*
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / pharmacology
  • Male
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Myeloid Cells / cytology
  • Myeloid Cells / drug effects*
  • Myeloid Cells / immunology
  • Tumor Microenvironment / drug effects


  • Immunosuppressive Agents
  • Fingolimod Hydrochloride