Eliminating METTL1‐mediated accumulation of PMN‐MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation

作者：Xuezhen Zeng, Guanrui Liao, Shumin Li, Haining Liu, Xiao Zhao, Shuang Li, Kai Lei, Shenghua Zhu, Zhihang Chen, Yi Zhao, Xuxin Ren, Tianhong Su, Alfred S.L. Cheng, Sui Peng, Shuibin Lin, Ji Wang, Shuling Chen, Ming Kuang · 发表于：Hepatology · 年份：2022 · DOI：10.1002/hep.32585 · 被引用次数：179 · 研究领域：RNA modifications and cancer、Epigenetics and DNA Methylation、Cancer, Hypoxia, and Metabolism

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains as high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m 7 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 immunohistochemistry and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b + CD15 + polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and decreased CD8 + T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-β2 translation to form the immunosuppressive environment by induction of myeloid-derived suppressor cell. Liver-specific overexpression or knockdown of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8 + T cell infiltration. Complete RFA successfully eliminated the tumor, whereas 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 c...