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MiR-24 induces human T cell exhaustion though mitochondria energy metabolic reprograming via suppressing MYC and FGF11

ABSTRACT: miR-24 induces human T cell exhaustion though mitochondria energy metabolic reprograming via suppressing MYC and FGF11

PROVIDER: PRJNA433927 | ENA |

REPOSITORIES: ENA

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miR-24 induces human T cell exhaustion though mitochondria energy metabolic reprograming via suppressing MYC and FGF11

Project description:Exhausted T cells (TExh) is a barrier for cancer immunotherapy, evidences demonstrate that transcriptional regulation is essential for TEX induction; however the factors that manipulate exhausted phenotype are largely unexplored. Here we showed that the microRNA (miR)-24, previously established to be enriched in eoxosmes from nasopharyngeal carcinoma (NPC) cells and promote T cell dysfunction, induced T cells to express high level of TIM-3, PD-1 and CD39 but to display low IFNg and GrB secretion and diminished proliferation ability ( a TExh phenotype) through inhibiting energy metabolism in vitro. Forced miR-24 expression inhibited ATP production through mitochondrial oxidative phosphorylation, while blockade of endogenous miR-24 the mitochondrial formation became massive and tubular and the levels of mitochondrial constituent proteins including Mfn1, Mfn2, P-Drp1 and TOMM20 was increased in OKT-3 stimulated T cells. MiR-24-mediated TEX and mitochondria metabolism reprogramming were regulated by suppressing MYC and FGF11 expression. Moreover, MYC enhanced the FGF11 transcription to promote mitochondria ATP production. Importantly, clinical data showed an increased TEX phenotype in circuiting and tumor-infiltrating T cells from NPC patients. Thus, our findings support that inhibition of miR-24-mediated mitochondria metabolism reprogramming can be titrated to break TExh immune barrier in NPC immunotherapy.

2020-08-11 | GSE110523 | GEO

DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency.

Project description:DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency.

| PRJNA850793 | ENA

DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [polysome-seq]

Project description:DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [polysome-seq]

| PRJNA850796 | ENA

DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [RNA-seq]

Project description:DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [RNA-seq]

| PRJNA850794 | ENA

DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [Ribo-seq]

Project description:DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [Ribo-seq]

| PRJNA850795 | ENA

GDNPs reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment

Project description:Lines of evidence indicate that, immune checkpoints (ICs) inhibitors enhance T cell immune response to exert anti-tumor effects. However, T cell exhaustion is still a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear. In this study, we demonstrated that GDNPs reprogramed TAMs via reducing arginase-1 (ARG1) production. Moreover, normalized arginine metabolism ameliorate T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8+ T cells expansion. Together, these results provide new insights in understanding the mechanisms involved in reversing T cell exhaustion, which may facilitate the development of new therapeutic strategy for cancer treatment.

2023-12-06 | GSE241285 | GEO

Transcriptome differences in HCC infiltrated CD8+ T cells in effector and exhaustion state

Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.

2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress

Lymphopenia-induced T cell exhaustion in STING gain-of-function mouse model

Project description:STING gain-of-function (GOF) mutations lead to T cell lymphopenia, in the context of severe combined immunodeficiency (SCID) for STING GOF V154M mice. This T cell lymphopenia, which is of central origin, has been described as type I IFN independent and associated with dysfunctions of the rare mature T cells found in the periphery. To better describe the biological mechanisms of these dysfunctions, we performed a transcriptomic analysis by RNA-seq on sorted splenic CD4+ and CD8+ mature T cells from STING GOF mice. We highlighted an unexpected T cell exhaustion phenotype that could partly explain their dysfunctions. Acquired very early in life, but only once the peripheral environment is reached, the phenotype appeared to depend neither on type I IFNs, nor on the intrinsic activation of STING in T or stromal cells. Mechanistically, the few mature T cells reaching the periphery seem to be rapidly impacted by the lymphopenic environment through increased antigenic and IL-7 stimulations that could lead to their exhaustion. By using STING GOF long term-hematopoietic stem cells (LT-HSC) transplantations with supportive wild-type bone marrow (BM) cells, we prevented the T cell exhaustion of STING GOF T cells in the resulting non lymphopenic context. With the support of lymphopenic RAG1 hypomorphic mice developing the phenotype, our data uncover a lymphopenia-mediated T cell exhaustion mechanism in STING GOF mice, for which a synergistic effect of the mutation is also envisaged.

2024-01-07 | E-MTAB-13658 | biostudies-arrayexpress

Direct regulation of T cell exhaustion by NFAT [RNA-Seq]

Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Understanding the role of CA-RIT-NFAT1 in T cells

2015-02-13 | E-GEOD-64408 | biostudies-arrayexpress

Direct regulation of T cell exhaustion by NFAT [ChIP-Seq]

2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress

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