Inhibition of METTL3 results in a cell-intrinsic interferon response that enhances anti-tumour immunity [RNA-seq]

ABSTRACT: Therapies that enhance anti-tumour immunity have dramatically changed the natural history of a range of cancers. Consequently, leveraging non-overlapping mechanisms to further increase the immunogenicity of cancer cells remains a major priority. Here, using a novel inhibitor of the RNA methyltransferase, METTL3, we demonstrate that enzymatic inhibition and a global decrease in N6-methyladenosine (m6A) results in double stranded RNA formation and a profound cell-intrinsic interferon response. By monitoring nascent mRNA, we show that the downstream induction of interferon stimulated genes (ISG) is coupled to a global increase in mRNA stability due to decreased m6A. One of the primary sequelae of this process is an increased expression and stability of genes associated with antigen presentation via MHC-I3. With unbiased global CRISPR screens we demonstrate that components of dsRNA sensing and interferon signalling are the primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. As PDL1, a key immune checkpoint, is also induced by interferon3, we show in a range of immunocompetent mouse models that whilst METTL3 inhibition alone is equally efficacious to anti-PD1 therapy, the combination has far greater pre-clinical activity. Importantly, using SPLINTR barcoding4, we demonstrate at single clone resolution that anti-PD1 and METTL3 inhibition target distinct malignant clones and the combination of these therapies augment anti-tumour immunity to overcome clones insensitive to the single agents. Together these data provide the molecular and pre-clinical rationale for employing METTL3 inhibitors to promote anti-tumour immunity in the clinical setting.

ORGANISM(S): Mus musculus

PROVIDER: GSE217920 | GEO | 2023/10/12

REPOSITORIES: GEO