Department of Liver Surgery , Center of Hepato-Pancreato-Biliary Surgery , The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , Guangdong Province , China.
Institute of Precision Medicine , the First Affiliated Hospital , Sun Yat-sen University , Guangzhou , Guangdong Province , China.
Hepatology. 2023 Apr 1;77(4):1122-1138. doi: 10.1002/hep.32585. Epub 2022 Jul 8.
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).
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 cell population.
Our study sheds light on the pivotal role of METTL1 in modulating an immunosuppressive microenvironment and demonstrated that interrupting METTL1-TGF-β2-PMN-MDSC axis could be a therapeutic strategy to restore antitumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.
射频消融（RFA）是肝细胞癌（HCC）的重要治疗方法，但复发率与其他 HCC 治疗方法相当高。甲基转移酶 1（METTL1）是 m7G tRNA 修饰的酶，据报道可促进 HCC 的发展。在这里，我们评估了 METTL1 在塑造 RFA 不足（iRFA）后免疫抑制肿瘤微环境中的作用。
通过免疫组化和多重免疫荧光（mIF）染色，我们显示 METTL1 表达在 RFA 后复发性 HCC 中增强，伴随着 CD11b + CD15 + 多形核髓系来源的抑制性细胞（PMN-MDSC）增加和 CD8 + T 细胞减少。在机制上，热介导的 METTL1 上调增强了 TGF-β2 的翻译，通过诱导髓样来源的抑制性细胞形成免疫抑制环境。肝特异性过表达或敲低 Mettl1 显著影响 PMN-MDSC 的积累，随后影响 CD8 + T 细胞浸润。完全 RFA 成功消除了肿瘤，而 iRFA 治疗的小鼠表现出增强的肿瘤生长和转移，与 sham 手术相比，PMN-MDSC 积累增加，CD8 + T 细胞减少。通过抗 Ly6G 抗体、敲低肝癌内在的 Mettl1 或 Tgfb2 或阻断 TGF-β 信号中断 METTL1-TGF-β2-PMN-MDSC 轴，显著减轻了 iRFA 诱导的肿瘤进展，并恢复了 CD8 + T 细胞群体。
我们的研究揭示了 METTL1 在调节免疫抑制微环境中的关键作用，并表明中断 METTL1-TGF-β2-PMN-MDSC 轴可能是一种恢复抗肿瘤免疫和防止 RFA 治疗后 HCC 复发的治疗策略，值得进一步的临床研究。
