Shuang Li

The success of haematopoietic stem cell transplantation (HSCT) lies with the ability of the engrafting immune system to remove residual leukaemia cells via a graft versus leukaemia effect, caused either spontaneously post HSCT or via donor lymphocyte infusion. Graft versus leukaemia effects can also be initiated by allogeneic mismatched NK cells, antigen specific T cells and activated dendritic cells of leukemic origin. The history and further application of this graft versus leukaemia effect and the main mechanisms will be discussed and reviewed in this chapter.

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 cell population. CONCLUSIONS: 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.

Previous studies have shown that tumors can induce angiogenesis and lymphangiogenesis, which plays an important role in promoting hematogenous and lymphogenous spread. In recent years, the cancer stem cell (CSC) theory has emerged as an attractive hypothesis for tumor development and progression. The theory proposes that one small subset of cancer cells has the characteristics of stem cells. These CSCs have the capability of both self-renewal and differentiation into diverse cancer cells, which play a decisive role in maintaining capacity for malignant proliferation, invasion, metastasis, and tumor recurrence. CSCs are involved in tumor metastasis, however, the details, and the possible relationship of CSCs, angiogenesis, lymphangiogenesis, and tumor metastasis is still ambiguous. The aim of this report is to summarize current studies of CSCs and tumor metastasis at the cellular level, with the goal of bringing new insights into understanding the role of CSCs in tumor metastasis.