Format

Send to

Choose Destination
Oncogene. 2017 Jun 29;36(26):3760-3771. doi: 10.1038/onc.2017.2. Epub 2017 Feb 20.

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

Li Y1,2,3,4, Zhou T1,4, Wang Y1,5, Ning C1,6, Lv Z1, Han G1,4, Morris JC7, Taylor EN7, Wang R1,4, Xiao H1,4, Hou C1,4, Ma Y2, Shen B1,4, Feng J1,4, Guo R8, Li Y1,4, Chen G1,4.

Author information

1
Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
2
Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, People's Republic of China.
3
Department of Internal Medicine, People's Hospital of Luanchuan County, Luoyang, People's Republic of China.
4
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
5
Department of Hematology and Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People's Republic of China.
6
Department of Oncology, the 161st Hospital of the PLA, Wuhan, People's Republic of China.
7
School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
8
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

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.

PMID:
28218904
DOI:
10.1038/onc.2017.2
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center