Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity

AA Guirguis; Y Ofir-Rosenfeld; K Knezevic; W Blackaby; D Hardick; YC Chan; A Motazedian; A Gillespie; D Vassiliadis; EYN Lam; K Tran; B Andrews; ME Harbour; L Vasiliauskaite; CJ Saunders; G Tsagkogeorga; A Azevedo; J Obacz; ES Pilka; M Carkill; L Macpherson; EN Wainwright; B Liddicoat; BJ Blyth; MR Albertella; O Rausch; MA Dawson

Journal article

Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity

AA Guirguis, Y Ofir-Rosenfeld, K Knezevic, W Blackaby, D Hardick, YC Chan, A Motazedian, A Gillespie, D Vassiliadis, EYN Lam, K Tran, B Andrews, ME Harbour, L Vasiliauskaite, CJ Saunders, G Tsagkogeorga, A Azevedo, J Obacz, ES Pilka, M Carkill Show all

Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2023

DOI: 10.1158/2159-8290.CD-23-0007

Abstract

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 media-tors that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhib..

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University of Melbourne Researchers

Chih Chan Author

Ali Motazedian Author

Dane Vassiliadis Author

Enid Lam Author

Related Projects (1)

INTERNATIONAL RESEARCH SCHOLARS PROGRAM

Grants

Awarded by Leukemia and Lymphoma Society

Funding Acknowledgements

We thank the Flow Cytometry core facility and the Molecular Genomics Core at the Peter MacCallum Cancer Centre as well as S. Jackson, J. Schreuders, R. Walker, K. Warren, K. Jhuang, T. Gulati, K. Simpson, and T. Semple for their technical contributions to this project. We thank Elliott Bayle and Beth Thomas from Storm Therapeutics Ltd for editing the medicinal and structural chemistry sections of the manuscript. We thank the following funders for fellowship, scholarship, and grant support: Cancer Council Victoria, the Sir Edward Dunlop Research Fellowship, NHMRC Investigator Grant 1196749, the mRNA Victoria Research Acceleration Fund, Howard Hughes Medical Institute International Research Scholarship 55008729 (M.A. Dawson), a VCA Mid-Career Research Fellowship (E.Y.N. Lam), and The Leukemia & Lymphoma Society, fellowship #3411-22 (D. Vassiliadis). This research was also funded in part by the NHMRC grants 1085015/1106444 (M.A. Dawson) and 1128984 (M.A. Dawson).