METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity.

Abstract

Although immunotherapy improves clinical outcomes in several types of malignancies, as an immunologically 'cold' tumor, pancreatic ductal adenocarcinoma (PDAC) is arrantly resistant to immunotherapy. However, the role of N6-methyladenosine (m6A) modification in the immune microenvironment of PDAC is still poorly understood. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify differentially expressed m6A related enzymes. The biological role and mechanism of METTL3 in PDAC growth and metastasis were determined in vitro and in vivo. RNA-sequencing and bioinformatics analysis were used to identify signaling pathways involved in METTL3. Western blot, m6A dot blot assays, co-immunoprecipitation, immunofluorescence, and flow cytometry were used to explore the molecular mechanism. Here, we demonstrate that METTL3, the key regulator of m6A modification, is downregulated in PDAC, and negatively correlates with PDAC malignant features. Elevated METTL3 suppresses PDAC growth and overcomes resistance to immune checkpoint blockade. Mechanistically, METTL3 promotes the accumulation of endogenous double-stranded RNA (dsRNA) through protecting m6A-transcripts from further Adenosine-to-inosine (A-to-I) editing. The dsRNA stress activates RIG-I-like receptors (RLRs) to enhance anti-tumor immunity, finally suppressing PDAC progression. Our findings indicate that tumor cell-intrinsic m6A modification participates in the regulation of tumor immune landscape. Adjusting the m6A level may be an effective strategy to overcome the resistance to immunotherapy and increase responsiveness to immunotherapy in PDAC.