Data from Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity
Year: 2024
Type: other
Abstract: Therapies that enhance anti-tumour immunity have altered the natural history of many cancers. Consequently, leveraging non-overlapping 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 formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signalling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that whilst METTL3 inhibition is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Using SPLINTR barcoding, we demonstrate that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies overcome clones insensitive to the single agents. These data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinic.
Authors: Andrew A. Guirguis, Yaara Ofir-Rosenfeld, Kathy Knezevic, Wesley Blackaby, David Hardick, Yih-Chih Chan, Ali Motazedian, Andrea Gillespie, Dane Vassiliadis, Enid YN. Lam, Kevin Tran, Byron Andrews, Michael E. Harbour, Lina Vasiliauskaite, Claire J. Saunders, Georgia Tsagkogeorga, Aleksandra Azevedo, Joanna Obacz, Ewa S. Pilka, Marie Carkill, Laura MacPherson, Elanor N. Wainwright, Brian Liddicoat, Benjamin J. Blyth, Mark R. Albertella, Oliver Rausch, Mark A. Dawson
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402806496