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

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

PROVIDER: PRJNA901397 | ENA |

REPOSITORIES: ENA

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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 [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 anti-tumour immunity [CRISPR screen]

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

| PRJNA1034972 | ENA

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]

| PRJNA901404 | ENA

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

2024-01-06 | GSE252537 | GEO

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.

2024-01-14 | GSE252960 | 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]

| PRJNA1061135 | ENA

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

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

| PRJNA1063316 | ENA

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-12 | GSE217923 | GEO

mRNA circularization by METTL3-eIF3h enhances translation

Project description:N6-methyladenosine (m6A) modification of mRNA catalyzed by METTL3 is enriched at a subset of stop codons. METTL3 can promote translation but the mechanism and widespread relevance remain unknown. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon supporting a mRNA looping mechanism for ribosome recycling and translational control. Electron microscopy revealed the topology of individual polyribosomes with single METTL3 foci found in close proximity to 5’ cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs, including BRD4 that are also m6A-modified in human primary lung tumors. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes, and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mRNA looping mechanism of translation control and identify METTL3-eIF3h as a potential cancer therapeutic target.

2018-09-21 | GSE117299 | GEO

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