Dataset Information

Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells.

ABSTRACT: FOXP3+ regulatory T cell (Treg) based cellular therapies represent promising therapeutic options in autoimmunity, allergy, transplantation and prevention of Graft Versus Host (GVH) Disease. Among human FOXP3-expressing CD4+T cells, only the CD45RA+ naïve Treg (nTreg) subset is suitable for in vitro expansion. However, FoxP3 expression decays in cells using currently described culture protocols. Rapamycin alone was not able to prevent FOXP3 loss in nTregs cells, as only a half of them maintained FOXP3 expression after 14 days of culture. In contrast we report a novel combined drug regimen that can drastically stabilize FOXP3 expression in cultured Tregs. IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors act in synergy to allow expansion of human regulatory T cells with sustained high expression of FOXP3 and CD15s with potent suppressive capacities in vitro and control of murine xeno-GVH reactions. Of note, an additional subsequent infusion of expanded nTreg cells did not improve survival of mice. Combination of IL-2, rapamycin, histone deacetylase and DNA methyltransferase inhibitors is optimal for the expansion in vitro of pure effective nTreg maintaining high levels of FOXP3 for therapeutic purposes.

SUBMITTER: Miyara M

PROVIDER: S-EPMC5739596 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells.

Miyara Makoto M Chader Driss D Burlion Aude A Goldstein Jérémie J Sterlin Delphine D Norol Françoise F Trebeden-Nègre Hélène H Claër Laetitia L Sakaguchi Shimon S Marodon Gilles G Amoura Zahir Z Gorochov Guy G

Oncotarget 20160728 62

FOXP3+ regulatory T cell (Treg) based cellular therapies represent promising therapeutic options in autoimmunity, allergy, transplantation and prevention of Graft Versus Host (GVH) Disease. Among human FOXP3-expressing CD4+T cells, only the CD45RA+ naïve Treg (nTreg) subset is suitable for in vitro expansion. However, FoxP3 expression decays in cells using currently described culture protocols. Rapamycin alone was not able to prevent FOXP3 loss in nTregs c ...[more]

PMID: 29285209

Similar Datasets

Project description:BackgroundTriple negative breast cancer (TNBC) is an aggressive neoplasia with no effective therapy. Our laboratory has developed a unique TNBC cell model presenting epithelial mesenchymal transition (EMT) a process known to be important for tumor progression and metastasis. There is increasing evidence showing that epigenetic mechanisms are involved in the activation of EMT. The objective of this study is to epigenetically reverse the process of EMT in TNBC by using DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi).MethodsWe evaluated the antitumor effect of three DNMTi and six HDACi using our TNBC cell model by MTT assay, migration and invasion assay, three dimensional culture, and colony formation assay. We then performed the combined treatment both in vitro and in vivo using the most potent DNMTi and HDACi, and tested the combined treatment in a panel of breast cancer cell lines. We investigated changes of EMT markers and potential signaling pathways associated with the antitumor effects.ResultsWe showed that DNMTi and HDACi can reprogram highly aggressive TNBC cells that have undergone EMT to a less aggressive phenotype. SGI-110 and MS275 are superior to other seven compounds being tested. The combination of SGI with MS275 exerts a greater effect than single agent alone in inhibiting cell proliferation, motility, colony formation, and stemness of cancer cells. We also demonstrated that MS275 and the combination of SGI with MS275 exert in vivo antitumor effect. We revealed that the combined treatment synergistically reverses EMT through inhibiting EpCAM cleavage and WNT signaling, suppressing mutant p53, ZEB1, and EZH2, and inducing E-cadherin, apoptosis, as well as histone H3 tri-methylation.ConclusionsOur study showed that DNMTi and HDACi exert antitumor activity in TNBC cells partially by epigenetically reprograming EMT. Our findings strongly suggest that TNBC is sensitive to epigenetic therapies. Therefore, we propose a new strategy to treat TNBC by using the combination of SGI-110 with MS275, which exerts superior antitumor effects by simultaneously targeting multiple pathways.

Dataset Information

Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells.

Publications

Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets