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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 04, 2023 |
| Title |
Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [CRISPR screen] |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
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.
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| Overall design |
CRISPR screen using the Brie library on B16 cells co-cultured with OT-I cells and in the presence of Mettl3 inhibitors
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| Contributor(s) |
Dawson MA, Guirguis AA |
| Citation(s) |
37548590 |
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| Submission date |
Nov 02, 2023 |
| Last update date |
Feb 05, 2024 |
| Contact name |
Mark Dawson |
| E-mail(s) |
mark.dawson@petermac.org
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| Organization name |
Peter MacCallum Cancer Centre
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| Department |
Cancer Research
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| Street address |
305 Grattan Street
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| City |
Melbourne |
| ZIP/Postal code |
3000 |
| Country |
Australia |
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| Platforms (1) |
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| Samples (11)
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| GSM7879966 |
B16 cas9 cells, co-cultured with OT-I cells 1:1 (E:T), 20 μmol/L Mettl3i |
| GSM7879967 |
B16 cas9 cells, co-cultured with OT-I cells 1:1 (E:T), DMSO |
| GSM7879968 |
B16 cas9 cells, co-cultured with OT-I cells 1:20 (E:T), 20 μmol/L Mettl3i |
| GSM7879969 |
B16 cas9 cells, co-cultured with OT-I cells 1:20 (E:T), DMSO |
| GSM7879970 |
B16 cas9 cells, co-cultured with OT-I cells 1:5 (E:T), 20 μmol/L Mettl3i |
| GSM7879971 |
B16 cas9 cells, co-cultured with OT-I cells 1:5 (E:T), 5 μmol/L Mettl3i |
| GSM7879972 |
B16 cas9 cells, co-cultured with OT-I cells 1:5 (E:T), DMSO |
| GSM7879973 |
B16 cas9 cells, 20 μmol/L Mettl3i |
| GSM7879974 |
B16 cas9 cells, 5 μmol/L Mettl3i |
| GSM7879975 |
B16 cas9 cells, DMSO |
| GSM7879976 |
B16 cas9 cells, early time point |
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| This SubSeries is part of SuperSeries: |
| GSE217923 |
Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity |
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| Relations |
| BioProject |
PRJNA1034972 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE246837_RAW.tar |
7.1 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
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