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Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [QuantSeq 3’ mRNA-Seq]

ABSTRACT: Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [QuantSeq 3’ mRNA-Seq]

PROVIDER: PRJNA1063316 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27482760.fastq.gz	Fastqsanger.gz
	SRR27482761.fastq.gz	Fastqsanger.gz
	SRR27482762.fastq.gz	Fastqsanger.gz
	SRR27482763.fastq.gz	Fastqsanger.gz
	SRR27482764.fastq.gz	Fastqsanger.gz

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Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [QuantSeq 3’ mRNA-Seq]

Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyltransferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the molecular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.

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Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [ONT direct RNA-seq]

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Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [CRISPR screen]

Project description:Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl-transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti-PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole-cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic.

2023-11-04 | GSE246837 | GEO

Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [ONT direct RNA-seq]

Project description:Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity [ONT direct RNA-seq]

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Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity

Project description:Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity

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Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [RNA-seq]

Project description:Therapies that enhance anti-tumour immunity have dramatically changed the natural history of a range of cancers. Consequently, leveraging non-overlapping mechanisms to further increase the immunogenicity of cancer cells remains a major priority. Here, using a novel inhibitor of the RNA methyltransferase, METTL3, we demonstrate that enzymatic inhibition and a global decrease in N6-methyladenosine (m6A) results in double stranded RNA formation and a profound cell-intrinsic interferon response. By monitoring nascent mRNA, we show that the downstream induction of interferon stimulated genes (ISG) is coupled to a global increase in mRNA stability due to decreased m6A. One of the primary sequelae of this process is an increased expression and stability of genes associated with antigen presentation via MHC-I3. With unbiased global CRISPR screens we demonstrate that components of dsRNA sensing and interferon signalling are the primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. As PDL1, a key immune checkpoint, is also induced by interferon3, we show in a range of immunocompetent mouse models that whilst METTL3 inhibition alone is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Importantly, using SPLINTR barcoding4, we demonstrate at single clone resolution that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies augment anti-tumour immunity to overcome clones insensitive to the single agents. Together these data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinical setting.

2023-10-12 | GSE217920 | GEO

Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [RNA-seq]

Project description:Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [RNA-seq]

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Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [CRISPR screen]

Project description:Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [CRISPR screen]

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METTL3 promotes translation in human cancer cells

Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells

2016-07-03 | E-GEOD-76367 | biostudies-arrayexpress

METTL3 KD in HepG2 cells

Project description:To gain insight into possible processes that require m6A for their function, METTL3 was knocked down (KD) in HepG2 cells by siRNA transfections Differential expression analysis of METTL3 KD versus mock-transfected HepG2 cells, in 2 biological replicates

2012-04-25 | E-GEOD-37001 | biostudies-arrayexpress

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