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.

Protein phosphatase 2A and tau: an orchestrated ‘Pas de Deux’

“…Pharmaceutically targeting SET to ‘disinhibit’ PP2A catalytic subunit could also pose significant side effects. For instance, FTY720 was found to potentially increase the risk for malignancies in recipients (For instance, see ), and apolipoprotein E‐mimetic peptides downregulate p38 activity .…”

Multiple Sclerosis Treatment and Melanoma Development

“…Taken together, our in vitro data indicate that in general neither fingolimod nor natalizumab directly act on melanoma cells to prompt proliferation or invasion but have instead an antitumorigenic action. A possible indirect action could be rather executed by fingolimod through induction of VEGF-A expression and recruitment of immune-suppressive MDSCs [29] and by natalizumab through impairment of NK cell functions [32]. Therefore, treatment with these drugs can modify tumor microenvironment towards an immune-suppressive, proangiogenic one, favoring melanoma progression.…”

“…Moreover, fingolimod induces apoptosis in vitro in mouse melanoma cells and blocks metastasis spreading both in a syngeneic mouse model [27] or in canine melanoma [28]. However, a protumorigenic role of fingolimod was also proposed, with this drug acting by enhancing accumulation of myeloid-derived suppressor cells (MDSCs) around the tumor lesion [29].…”

Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks

“…These cells account for a major subpopulation of monocytes in the blood of GBM patients, and are abundant in the GBM microenvironments [268,269]. It was demonstrated that S1P can induce an increase in MDSC activity in different solid cancers [270], and thus reduce the immune response. Indeed, the S1P activation of the ERK1/2 MAPK pathway coupled to S1P3 induced an increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in an enrichment of MDSCs in the tumor niche, and autocrine stimulation of immunosuppressive functions of these cells [270].…”

“…It was demonstrated that S1P can induce an increase in MDSC activity in different solid cancers [270], and thus reduce the immune response. Indeed, the S1P activation of the ERK1/2 MAPK pathway coupled to S1P3 induced an increased expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in an enrichment of MDSCs in the tumor niche, and autocrine stimulation of immunosuppressive functions of these cells [270]. These results show that S1P3 activation by S1P can stimulate MDSC immunosuppressive activity in the tumor niche.…”