Toll-Like Receptor 9 (TLR9) stimulation selectively triggers the formation of a cell cluster termed intrahepatic myeloid aggregation for T cell expansion" (iMATE) in a mouse chronic viral hepatitis model. iMATE expands cytotoxic T cells and controls viral hepatitis infection. The liver-specific immune response prompted this investigation of whether the effect could control tumor growth in the murine hepatic tumor model. Murine hepatic BNL cells were used to establish an orthotropic liver tumor model. We found that intravenous infusion of TLR 9 agonist, CpG oligodeoxynucleotide (ODN) induced iMATE formation in non-tumor parts of liver and suppressed the murine BNL tumor growth. The ratio of intra-tumor CD8+ T cells have increased after CpG ODN. These cells expressed higher levels of effector and checkpoint molecules, and produce more Th1 cytokine upon ex vivo stimulation. The CD11b+Ly6ChiLy6G - subset of CD11b+ myeloid cells in the tumor microenvironment has increased. Both CD11b+Ly6ChiLy6G - and CD11b+Ly6CloLy6G+ subsets expressed higher level of interferon-gamma post CpG ODN treatment, although still presented a suppressive phenotype. Their suppressive ability was decreased, instead, the targeted CD8+ T cell proliferation was promoted at a higher dose of CD11b+Ly6ChiLy6G- cells. The phenomenon was further proven in DEN induced liver tumor model. In conclusion, systemic CpG ODN treatment induced iMATE formation that expanded effector CD8+ T cells to control tumor growth in the mouse hepatic tumor model. This novel strategy provides a new rationale for liver-specific tumor immunotherapy.

中文翻译：

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诱导肝脏特异性肝内骨髓细胞聚集可扩大 CD8 T 细胞并抑制小鼠肝癌的生长。

在小鼠慢性病毒性肝炎模型中，Toll 样受体 9 (TLR9​​) 刺激选择性触发称为“肝内骨髓聚集 T 细胞扩增”(iMATE) 的细胞簇的形成。iMATE 扩增细胞毒性 T 细胞并控制病毒性肝炎感染。 -特异性免疫反应促使我们研究该效应是否可以控制小鼠肝肿瘤模型中的肿瘤生长。利用小鼠肝BNL细胞建立正交异性肝肿瘤模型。我们发现静脉输注TLR 9激动剂CpG寡脱氧核苷酸（ODN） ) 诱导肝脏非肿瘤部分 iMATE 形成并抑制小鼠 BNL 肿瘤生长。CpG ODN 后肿瘤内 CD8+ T 细胞比例增加。这些细胞表达更高水平的效应子和检查点分子，并产生更多 Th1 细胞因子CD11b+Ly6ChiLy6G - 肿瘤微环境中 CD11b+ 骨髓细胞的子集有所增加。CD11b+Ly6ChiLy6G - 和 CD11b+Ly6CloLy6G+ 子集在 CpG ODN 治疗后表达更高水平的干扰素-γ，尽管仍然呈现抑制表型。在较高剂量的CD11b+Ly6ChiLy6G-细胞下，它们的抑制能力降低，相反，靶向CD8+T细胞增殖得到促进。这一现象在DEN诱导的肝肿瘤模型中得到进一步证实。总之，全身 CpG ODN 治疗诱导 iMATE 形成，从而扩大效应 CD8+ T 细胞以控制小鼠肝肿瘤模型中的肿瘤生长。这种新策略为肝脏特异性肿瘤免疫治疗提供了新的原理。