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

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

Author(s): Guirguis, AA; Ofir-Rosenfeld, Y; Knezevic, K; Blackaby, W; Hardick, D; Chan, YC; Motazedian, A; Gillespie, A; Vassiliadis, D; Lam, EYN; Tran, K; Andrews, B; Harbour, ME; Vasiliauskaite, L; Saunders, CJ; Tsagkogeorga, G; Azevedo, A; Obacz, J; Pilka, ES; Carkill, M; MacPherson, L; Wainwright, EN; Liddicoat, B; Blyth, BJ; Albertella, MR; Rausch, O; Dawson, MA;
Details: Publication Year 2023,Volume 13,Issue #10,Page 2228-2247
Journal Title: Cancer Discovery
Publication Type: Research 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 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. SIGNIFICANCE: 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.
Publisher: American Association for Cancer Research
Keywords: Animals; Mice; *Interferons/genetics; *Methyltransferases/genetics/metabolism; RNA, Double-Stranded
Department(s): Laboratory Research; Clinical Haematology
PubMed ID: 37548590
Publisher's Version: https://doi.org/10.1158/2159-8290.CD-23-0007
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-30 06:21:00

Last Modified: 2023-11-30 06:21:26