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Figure S3 from Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity

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posted on 2023-10-05, 07:20 authored by Andrew A. Guirguis, Yaara Ofir-Rosenfeld, Kathy Knezevic, Wesley Blackaby, David Hardick, Yih-Chih Chan, Ali Motazedian, Andrea Gillespie, Dane Vassiliadis, Enid Y.N. 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

METTL3 KD in B16 cell line

Funding

Cancer Council Victoria

Sir Edward ‘Weary’ Dunlop Medical Research Foundation

National Health and Medical Research Council (NHMRC)

mRNA Victoria Research Acceleration Fund

Howard Hughes Medical Institute (HHMI)

Victorian Cancer Agency (VCA)

Leukemia and Lymphoma Society (LLS)

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ARTICLE 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 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. This work demonstrates that METTL3 inhibition stimulates a cell-intrinsic interferon response through dsRNA formation. This immunomodulatory mechanism is distinct from current immunotherapeutic agents and provides the molecular rationale for combination with anti–PD-1 immune-checkpoint blockade to augment antitumor immunity.This article is featured in Selected Articles from This Issue, p. 2109

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