Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents HCC recurrence after radiofrequency ablation

Hepatology. 2022 May 22. doi: 10.1002/hep.32585. Online ahead of print.

Abstract

Background and aims: Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m7 G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA).

Approach and results: By IHC and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b+ CD15+ PMN-MDSCs and decreased CD8+ T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-β2 translation to form the immunosuppressive environment by induction of MDSC. Liver specific overexpression or knockout of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8+ T cell infiltration. Complete RFA (cRFA) successfully eliminated the tumor, while iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8+ T cells compared to sham surgery. Interrupting METTL1-TGF-β2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2, or TGF-β signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8+ T cell population.

Conclusions: Our study sheds light on a previsouly unrevealed role of METTL1 in modulating an immunosuppressive microenvironment, and demonstrated that interrupting METTL1- TGF-β2-PMN-MDSC axis could be a novel therapeutic strategy to restore anti-tumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.