title: The protumorigenic potential of FTY720 by promoting extramedullary hematopoiesis and MDSC accumulation.
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.
authors.affiliation: 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.|Department of Internal Medicine, People's Hospital of Luanchuan County, Luoyang, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|Department of Hematology and Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|Department of Oncology, the 161st Hospital of the PLA, Wuhan, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Ning
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Han
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: School of Chemistry, University of New South Wales, Sydney, NSW, Australia.
authors.forename: E N
authors.initials: EN
authors.lastname: Taylor
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Hou
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: B
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D000068876:Fingolimod Hydrochloride / Q000009:adverse effects* / Q000494:pharmacology; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride