Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+and CD4+effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.
肝细胞癌（HCC）是最常见的原发性肝癌，全球范围内其发病率持续上升且死亡率居高不下。尽管诊断技术有所进步且临床前研究展现出良好前景，但目前针对HCC仍缺乏成熟的根治性治疗方案。近年来对肿瘤微环境相互作用机制的深入理解，使免疫治疗成为科研焦点，并彻底改变了晚期HCC患者的治疗格局。然而，现有免疫治疗方案仅能使少数HCC患者获益，这促使我们需要探索能提高患者应答率的新靶点，并将其纳入新型联合治疗方案。 糖皮质激素诱导的TNFR相关蛋白（GITR）属于TNFR超家族成员，当其配体GITRL激活时，可促进CD8+和CD4+效应T细胞功能，同时抑制调节性T细胞功能。目前GITR已被视为多种肿瘤的潜在免疫治疗靶点，尤其是在联合程序性细胞死亡蛋白-1（PD-1）阻断治疗时。在肝脏疾病研究中发现，肝祖细胞中GITR的高表达与肝细胞分化受损及祖细胞介导的肝再生能力下降相关。结合现实世界数据证实的抗肿瘤效应，以及近期临床前模型揭示其在癌前肝病中的作用机制，将GITR纳入HCC治疗体系的理论构想应运而生。本文旨在综述当前证据，探讨靶向GITR/GITRL信号通路作为晚期HCC潜在治疗策略的科学依据。
Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma
肿瘤(癌症)患者之家