T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), mediating immune exhaustion in tumor microenvironment, has become a promising target for tumor therapy. However, the exact mechanisms for tumor cell-intrinsic Tim-3 in tumor development and its potential contribution in Tim-3-targeted therapy strategy have not been elucidated yet. In this study, we showed that human liver cancer tissues contained high ratio of Tim-3-expressing hepatocytes, and cytokines rich in tumor microenvironment and HBV involved in Tim-3 upregulation in malignant hepatocytes. We demonstrated that hepatocyte-specific Tim-3 overexpression enhances tumor cell growth, whereas Tim-3 inhibition on malignant hepatocytes by anti-Tim-3 antibodies or RNAi suppresses tumor growth both in vitro and in Tim-3 knockout mice. Mechanistically, the hepatocyte-Tim-3 receptor activates NF-κB phosphorylation, which in turn stimulates IL-6 secretion and STAT3 phosphorylation. Our results identify tumor cell-intrinsic functions of Tim-3 in tumorigenesis and suggest that blocking Tim-3 in tumor cells might contribute to the clinical efficacy of anti-Tim-3 antibody treatment in the future tumor therapy.

中文翻译：

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肿瘤细胞固有的Tim-3通过NF-κB/ IL-6 / STAT3轴促进肝癌。

在肿瘤微环境中介导免疫力衰竭的T细胞免疫球蛋白和含粘蛋白结构域3（Tim-3）已成为肿瘤治疗的有希望的目标。然而，尚未阐明肿瘤细胞内在的Tim-3在肿瘤发展中的确切机制及其在Tim-3靶向治疗策略中的潜在作用。在这项研究中，我们表明人肝癌组织中含有高比例的表达Tim-3的肝细胞，而富含肿瘤微环境和HBV的细胞因子参与了恶性肝细胞中Tim-3的上调。我们证明了肝细胞特异性的Tim-3过表达增强了肿瘤细胞的生长，而抗Tim-3抗体或RNAi对Tim-3对恶性肝细胞的抑制作用在体外和在Tim-3基因敲除小鼠中均抑制了肿瘤的生长。机械上，肝细胞Tim-3受体激活NF-κB磷酸化，进而刺激IL-6分泌和STAT3磷酸化。我们的结果确定了Tim-3在肿瘤发生中的肿瘤细胞内在功能，并提示在肿瘤细胞中阻断Tim-3可能有助于在未来的肿瘤治疗中抗Tim-3抗体治疗的临床疗效。