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

  • Cancer Discov. 2023 Oct 5;13(10):2228-2247. doi: 10.1158/2159-8290.CD-23-0007.
Andrew A Guirguis  #  1  2  3 ,  Yaara Ofir-Rosenfeld  #  4 ,  Kathy Knezevic  1 ,  Wesley Blackaby  4 ,  David Hardick  4 ,  Yih-Chih Chan  1  2 ,  Ali Motazedian  1  2 ,  Andrea Gillespie  1 ,  Dane Vassiliadis  1  2 ,  Enid Y N Lam  1  2 ,  Kevin Tran  1  2 ,  Byron Andrews  4 ,  Michael E Harbour  4 ,  Lina Vasiliauskaite  4 ,  Claire J Saunders  4 ,  Georgia Tsagkogeorga  4  5 ,  Aleksandra Azevedo  4 ,  Joanna Obacz  4 ,  Ewa S Pilka  6 ,  Marie Carkill  7 ,  Laura MacPherson  1  2 ,  Elanor N Wainwright  1  2 ,  Brian Liddicoat  1  2 ,  Benjamin J Blyth  1  2 ,  Mark R Albertella  4 ,  Oliver Rausch  #  4 ,  Mark A Dawson  #  1  2  3  8
Affiliations
  • 1. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
  • 3. Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
  • 4. Storm Therapeutics Ltd, Cambridge, United Kingdom.
  • 5. Milner Therapeutics Institute, University of Cambridge, Cambridge, United Kingdom.
  • 6. Evotec (UK) Ltd, Abingdon, United Kingdom.
  • 7. Charles River Laboratories, Portishead, United -Kingdom.
  • 8. Centre for Cancer Research, University of Melbourne, Melbourne, -Victoria, Australia.
  • # Contributed equally.
PMID: 37548590 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 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.

Products