Tofacitinib Facilitates the Expansion of Myeloid‐Derived Suppressor Cells and Ameliorates Arthritis in SKG Mice

Nishimura, Keisuke; Saegusa, Jun; Matsuki, Fumichika; Akashi, Koichi; Kageyama, Goichi; Morinobu, Akio

doi:10.1002/art.39007

Cited by 38 publications

(34 citation statements)

References 37 publications

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“…Their specific targeting of JAK/STAT signaling makes them interesting candidates to target STAT signaling in MDSCs and to be used in combination with immunotherapy in anticancer regimes. However, the only study available on these drugs is in the context of rheumatoid arthritis and in that setting tofacitinib surprisingly resulted in the expansion of MDSCs 87 . On the other hand, in a melanoma mouse model, specific JAK inhibition with the experimental compound AZD1480 reduced MDSC frequencies, but it also enhanced their suppressive capacity 88 .…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Improving cancer immunotherapy by targeting the STATe of MDSCs

et al. 2016

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Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions. Interestingly, several drugs used for non-cancerous indications and natural compounds similarly inhibit MDSCs by STAT inhibition, but have fewer side effects than anticancer drugs. Therefore, they show great potential for combination strategies with immunotherapy.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Improving cancer immunotherapy by targeting the STATe of MDSCs

et al. 2016

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“…Arthritis developed 2 to 3 weeks later. The development and severity of arthritis were assessed using a previously described system for scoring clinical arthritis 45 . We administered 5 mg/kg intraperitoneal BrPA (each group was 4 mice) in a prevention study.…”

Section: Methodsmentioning

confidence: 99%

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

Okano

Saegusa

Nishimura

et al. 2017

Sci Rep

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Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.

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“…Another report showed similar results in CIA and antigen-induced arthritis models [ 35 ]. Nishimura et al found that tofacitinib, a JAK inhibitor, facilitates the expansion of MDSCs and ameliorates arthritis in SKG mice [ 36 ]. On the other hand, Zhang et al reported that MDSCs are pro-inflammatory and aggravate arthritis in CIA [ 37 ].…”

Section: Main Textmentioning

confidence: 99%

Myeloid-derived suppressor cells in non-neoplastic inflamed organs

2018

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BackgroundMyeloid-derived suppressor cells (MDSCs) are a highly heterogeneous population of immature myeloid cells with immunosuppressive function. Although their function in tumor-bearing conditions is well studied, less is known about the role of MDSCs in various organs under non-neoplastic inflammatory conditions.Main bodyMDSCs are divided into two subpopulations, G-MDSCs and M-MDSCs, and their distribution varies between organs. MDSCs negatively control inflammation in inflamed organs such as the lungs, joints, liver, kidneys, intestines, central nervous system (CNS), and eyes by suppressing T cells and myeloid cells. MDSCs also regulate fibrosis in the lungs, liver, and kidneys and help repair CNS injuries. MDSCs in organs are plastic and can differentiate into osteoclasts and tolerogenic dendritic cells according to the microenvironment under non-neoplastic inflammatory conditions.ConclusionThis article summarizes recent findings about MDSCs under inflammatory conditions, especially with respect to their function and differentiation in specific organs.

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Tofacitinib Facilitates the Expansion of Myeloid‐Derived Suppressor Cells and Ameliorates Arthritis in SKG Mice

Cited by 38 publications

References 37 publications

Improving cancer immunotherapy by targeting the STATe of MDSCs

Improving cancer immunotherapy by targeting the STATe of MDSCs

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation

Myeloid-derived suppressor cells in non-neoplastic inflamed organs

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