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Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming in vivo and in vitro.

ABSTRACT: Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming in vivo and in vitro.

PROVIDER: PRJNA678553 | ENA |

REPOSITORIES: ENA

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Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming

Project description:Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming

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Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming in vivo and in vitro

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Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming.

Project description:Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.

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Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming

Project description:Chimeric antigen receptor T (CAR T) cells targeting CD19 have achieved breakthroughs in the treatment of haematological malignancies, but many clinical studies have also shown that a proportion of patients relapse after remission.In this study, we designed CART treatment by DNMTi?dCART) inhibitor and found that dCAR T cells retained relatively potent antitumour activity compared with CAR T cell upon target antigen recognition. It may be associated with memory and anti-exhausion. Our transcriptional analysis underscores the potential of dCAR T cells.

2019-11-08 | GSE140107 | GEO

Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming in vivo and in vitro.

Project description:Chimeric antigen receptor T (CAR T) cells targeting CD19 have achieved breakthroughs in the treatment of haematological malignancies, but many clinical studies have also shown that a proportion of patients relapse after remission.In this study, we designed CART treatment by DNMTi（dCART) inhibitor and found that dCAR T cells retained relatively potent antitumour activity compared with CAR T cell upon target antigen recognition. It may be associated with memory and anti-exhausion. Our transcriptional analysis underscores the potential of dCAR T cells.

2020-11-16 | GSE161506 | GEO

Low-dose decitabine priming endows CAR T cells with enhanced and persistent anti-tumor potential by epigenetic reprogramming in vivo and in vitro

Project description:Chimeric antigen receptor T (CAR T) cells targeting CD19 have achieved breakthroughs in the treatment of haematological malignancies, but many clinical studies have also shown that a proportion of patients relapse after remission.In this study, we designed CART treatment by DNMTi（dCART) inhibitor and found that dCAR T cells retained relatively potent antitumour activity compared with CAR T cell upon target antigen recognition. It may be associated with memory and anti-exhausion. Our transcriptional analysis underscores the potential of dCAR T cells.

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Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

Project description:Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors. To test this hypothesis we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification (TRAP) to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. TRAP sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. We identified Gpr88as upregulated, and Metrn as downregulated. We confirmed a functional role for these genes wherein a GPR88 agonist causes pain only in primed mice, and established hyperalgesic priming is reversed by Meteorin. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming.

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Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models

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Low-dose decitabine modulates T cell homeostasis and restores immune tolerance in immune thrombocytopenia

Project description:Immune thrombocytopenia (ITP) is an acquired autoimmune disease triggered by abnormal T cell immunity, especially the impairment of regulatory T (Treg) cells and helper T (Th) cell subsets. Decitabine, a hypomethylating agent promoting cell differentiation at low dose, has been demonstrated the function of increasing the number of mature polyploidy megakaryocytes in ITP as well as Treg cells in allogeneic transplantation. Recently, our clinical study proved that decitabine was effective and safe in the management of adult ITP patients, and nearly half showed sustained responses. However, whether low-dose decitabine has the potential in restoring immune tolerance in ITP is unknown. In our in vitro studies, we identified that low-dose decitabine could promote the generation and differentiation and enhance the immunosuppressive function of Treg cells. Furthermore, low-dose decitabine alleviated thrombocytopenia and regained the balance of Treg/Th cell subsets in active murine models of ITP. For patients who received low-dose decitabine therapy and showed responses, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were depressed compared with the pretreatment levels. Finally, immunophenotyping and next-generation RNA sequencing analysis showed that low-dose decitabine restored T cell homeostasis and decreased the level of proinflammatory cytokines along with the downregulation of STAT3 and Akt in refractory ITP patients. Therefore, our data reveal the immunomodulatory effect of decitabine and provide unique insights into the sustained response achieved by decitabine in the management of ITP patients.

2020-07-21 | GSE154703 | GEO

Radiotherapy induces persistent innate immune reprogramming of microglia into a priming state

Project description:Radiotherapy induces persistent innate immune reprogramming of microglia into a priming state

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