Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany.
Institute for Experimental Molecular Imaging, University Hospital RWTH Aachen, 52074 Aachen, Germany.
Int J Mol Sci. 2022 Jul 23;23(15):8112. doi: 10.3390/ijms23158112.
Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and knockout mice () were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl) to induce fibrosis-associated HCCs. deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl-treated mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies.
肝细胞癌（HCC）是一种严重的健康负担。最近，肿瘤微环境导向的干预措施深刻改变了 HCC 治疗的格局。在本研究中，分析了趋化因子 CXCL10 在纤维化相关肝癌发生中的作用，特别关注其对肿瘤微环境形成的影响。使用二乙基亚硝胺（DEN）和四氯化碳（CCl）对 C57BL/6J 野生型（WT）和 敲除（）小鼠进行处理，以诱导纤维化相关 HCC。 缺陷通过减少肿瘤细胞增殖以及肿瘤血管生成和调节肿瘤相关细胞外基质组成来减弱肝癌发生。此外， 基因失活介导了肿瘤相关免疫反应的改变，并修饰了趋化因子/趋化因子受体网络。DEN/CCl 处理的 小鼠表现出促炎肿瘤微环境和组织中抗肿瘤免疫细胞的积累。 在 肿瘤免疫微环境中最显著的改变是抗肿瘤 T 细胞在侵袭性肿瘤边缘的大量积累。总之，我们的结果表明，CXCL10 对肿瘤微环境的几个特征具有非冗余的影响，特别是调节 HCC 中抗肿瘤免疫细胞的浸润。在肿瘤微环境靶向 HCC 治疗的时代，干扰 CXCL10 为进一步改善治疗策略提供了新的资产。
