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DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T-cells

ABSTRACT: DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T-cells

PROVIDER: PRJNA637641 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11938011.fastq.gz	Fastqsanger.gz
	SRR11938012.fastq.gz	Fastqsanger.gz
	SRR11938013.fastq.gz	Fastqsanger.gz
	SRR11938014.fastq.gz	Fastqsanger.gz
	SRR11938015.fastq.gz	Fastqsanger.gz

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DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T-cells

Project description:DNA hypomethylating agents (HMAs) induce Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. Yet, the direct effects of HMAs in immune cells remains less clear. Here, we demonstrate that HMA treatments can directly modulate the anti-tumor response and effector function of CD8+ T-cells. In vivo HMA treatment promotes CD8+ T-cell tumor infiltration and supresses tumor growth via CD8+ T-cell dependent activity. HMAs enhances primary human CD8+ T-cells activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T-cell activation related transcriptional networks, culminating with over-activation of NFATc1 short-isoforms. Mechanistically, demethylation of an intragenic CpG Island immediately downstream to the 3'UTR of the short isoform was associated with anti-sense transcription and alternative polyadenylation of NFATc1 short-isoforms. High-dimensional single-cell mass cytometry (CyTOF) analyses reveal a selective effect of HMAs on a subset of human CD8+ T-cell subpopulations, resulting in an increase in both number and abundance of a granzymeBhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.

2021-02-08 | GSE151917 | GEO

thermal proteome profiling of hypomethylating agents in infant ALL

Project description:thermal proteome profiling of hypomethylating agents in infant ALL for elucidation of their mode of action.

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents

Project description:Large-scale sequencing efforts in Clear cell renal cell carcinoma (ccRCC) have found a high prevalence of mutations in chromatin-related genes. Prominent within this group is SETD2, which is mutated in 15% of ccRCC and is associated with aggressive disease. SETD2 is a methyltransferase responsible for trimethylating lysine 36 on histone H3 (H3K36me3). Although it is not completely understood how SETD2 loss contributes to ccRCC tumorigenesis, it is thought that it reprograms the epigenetic landscape of the cell. Here we explore the impact that SETD2/H3K36me3 loss has on the DNA methylome in ccRCC cells. DNA methylation was measured using the EPIC DNA methylation assay in 786-O ccRCC cells and non-cancerous transformed proximal tubule kidney cells (HKC) with and without SETD2. Sensitivity to DNA hypomethylating agents was assessed by dose-response assay using 5-aza-2'-deoxycytidine. Apoptosis was measured via Annexin-V/PI staining by flow cytometry. Mitochondrial fitness was evaluated by electron microscopy and flow cytometry. Moreover, activity of 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, in was assessed in SETD2 WT/KO xenografts in NOD-Scid mice. SETD2 loss resulted in DNA hypermethylation in HKC cells and to a greater extent in 786-O. Dose-response assays showed that SETD2-null ccRCC cells are sensitive to 5-aza-2'-deoxycytidine. Furthermore, Annexin-V/PI staining revealed more apoptotic and necrotic cells in SETD2-null cells following 5-aza-2'-deoxycytidine treatment, which was rescued using a Caspase inhibitor. In addition, 5-aza-2'-deoxycytidine induced profound changes in mitochondria in SETD2-null cells, including loss of membrane potential and size reduction. Indeed, in vivo experiments verified increased SETD2-null xenografts’ sensitivity to 5-aza-2'-deoxycytidine. We show that SETD2 loss in ccRCC cells causes DNA hypermethylation, creating a synthetic lethal dependency with DNA hypomethylating agents.

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SETD2 loss sensitizes kidney cancer cells to DNA hypomethylating agents [methylation]

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Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia

Project description:The FDA-approved DNA hypomethylating agents (DHAs) like 5-azacytidine (5AC) and decitabine (DAC) demonstrate efficacy in the treatment of hematologic malignancies. Despite previous reports that showed histone acetylation changes upon using these agents, the exact mechanism underpinning these changes is unknown. In this study, we investigated the relative potency of the nucleoside analogs and non-nucleoside analogs DHAs on DNA methylation reversal using DNA pyrosequencing. Additionally, we screened their effect on the enzymatic activity of the histone deacetylase sirtuin family (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6) using both recombinant enzymes and nuclear lysates from leukemia cells. The nucleoside analogs (DAC, 5AC and zebularine) were the most potent DHAs and increased the enzymatic activity of SIRT6 without showing any significant increase in other sirtuin isoforms. ChIP-Seq analysis of bone marrow cells derived from six acute myeloid leukemia (AML) patients and treated with the nucleoside analog DAC induced genome-wide acetylation changes in H3K9, the physiological substrate for SIRT6. Data pooling from the six patients showed significant acetylation changes in 187 gene loci at different chromosomal regions including promoters, coding exons, introns and distal intergenic regions. Signaling pathway analysis showed that H3K9 acetylation changes are linked to AML-relevant signaling pathways like EGF/EGFR and Wnt/Hedgehog/Notch. To our knowledge, this is the first report to identify the nucleoside analogs DHAs as activators of SIRT6. Our findings provide a rationale against the combination of the nucleoside analogs DHAs with SIRT6 inhibitors or chemotherapeutic agents in AML due to the role of SIRT6 in maintaining genome integrity and DNA repair.

2020-07-28 | GSE152804 | GEO

Cytolytic CD8+ T cells infiltrate germinal centers to limit ongoing HIV replication in spontaneous controller lymph nodes

Project description:Follicular CD8+ T cells (fCD8) mediate surveillance in lymph node (LN) germinal centers against lymphotropic infections and cancers, but precise mechanisms by which these cells mediate immune control remain incompletely resolved. To address this, we investigated functionality, clonotypic compartmentalization, spatial localization, phenotypic characteristics, and transcriptional profiles of LN-resident virus-specific CD8+ T cells in persons who control HIV without medications. Antigen-induced proliferative and cytolytic potential consistently distinguished spontaneous controllers from noncontrollers. T cell receptor analysis revealed complete clonotypic overlap between peripheral and LN-resident HIV-specific CD8+ T cells. Transcriptional analysis of LN CD8+ T cells revealed gene signatures of inflammatory chemotaxis and antigen-induced effector function. In HIV controllers, the cytotoxic effectors perforin and granzyme B were elevated among virus-specific CXCR5+ fCD8s proximate to foci of HIV RNA within germinal centers. These results provide evidence consistent with cytolytic control of lymphotropic infection supported by inflammatory recruitment, antigen-specific proliferation, and cytotoxicity of fCD8s.

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