Li Zhu, Li Na, Li Fang, Zhou Zhihua, Sang Jiao, Chen Yanping, Han Qunying, Lv Yi, Liu Zhengwen
Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University Department of Infectious Diseases, Yanan University Affiliated Hospital, Yanan Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, Shaanxi, China.
Medicine (Baltimore). 2016 Dec;95(52):e5749. doi: 10.1097/MD.0000000000005749.
Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.
免疫检查点蛋白程序性死亡受体 1（PD-1）和含 T 细胞免疫球蛋白结构域和粘蛋白结构域分子 3（TIM-3）的表达及其基因多态性已分别被证明与乙型肝炎病毒（HBV）感染和肝细胞癌（HCC）相关。本研究同时检测了 171 例 HBV 相关 HCC 患者和 34 例 HBV 相关肝硬化患者肝组织中 PD-1 和 TIM-3 的表达以及 PD1 和 TIM3 基因多态性，并分析了它们之间的相关性。采用免疫组织化学法检测肝组织中 PD-1 和 TIM-3 的表达，以从外周血提取的基因组 DNA 为模板，使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测 PD1 rs10204525 和 TIM3 rs10053538 多态性的基因型。HCC 肿瘤组织肝浸润淋巴细胞中的 PD-1 和 TIM-3 表达均显著高于肿瘤邻近组织或肝硬化组织。PD-1 和 TIM-3 表达升高与更高的肿瘤分级显著相关。肿瘤组织与肿瘤邻近组织中 PD-1 和 TIM-3 表达水平之间存在显著正相关。肿瘤组织、肿瘤邻近组织和肝硬化组织中 PD-1 和 TIM-3 的表达与 PD1 和 TIM3 基因多态性显著相关，PD1 rs10204525 的 AA 基因型和 TIM3 rs10053538 的 GT+TT 基因型分别与 PD-1 和 TIM-3 表达显著增加相关。这些发现支持通过同时阻断 PD-1 和 TIM-3 提高免疫检查点靶向治疗效率并降低治疗耐药性的潜力，并提示将 PD1 rs10204525 和 TIM3 rs10053538 的基因型测定作为免疫检查点导向治疗生物标志物的潜力。
