Cai Xue, Yu Lihua, Liu Xiaoli, Yan Huiwen, Xie Yuqing, Pu Qing, Shang Zimeng, Wu Yuan, Jiang Tingting, Yang Zhiyun
Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People's Republic of China.
Beijing Shangdi Hospital, Beijing, 100085, People's Republic of China.
Onco Targets Ther. 2025 Apr 19;18:559-573. doi: 10.2147/OTT.S512838. eCollection 2025.
Nowadays, immune checkpoint blockade (ICB) therapy has become a milestone in immunotherapy for hepatocellular carcinoma (HCC). However, its clinical effectiveness remains low. Soluble (s) immune checkpoints (ICs), functional components of membrane ICs, are novel physiological immunomodulators. We investigated the prognostic value of sICs in patients of hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and provided clinical clues for potential new targets for future immunotherapy.
A total of 256 participants were included in this study. We compared the plasma levels of 14 sICs in healthy controls (HC), chronic hepatitis B (CHB), hepatitis B-related liver cirrhosis (HBV-LC), and HBV-HCC groups. COX and random survival forest (RSF) were used to select variables and construct a model to predict overall survival of patients with HBV-HCC. We evaluated the predictive efficacy and analyzed the correlations between sICs, clinical parameters, and membrane ICs.
The levels of 14 sICs in HBV-HCC were elevated compared to that in HC. The areas under the receiver operating characteristic values of 1-, 2-, and 3-year survival predicted by the RSF model were 0.96, 0.85, and 0.81 in the training set, and 0.91, 0.80, and 0.71 in the validation set. The model could adapt to different event distributions and clinical staging systems. Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR), soluble programmed cell death-ligand 1 (sPD-L1) and soluble T cell immunoglobulin and mucin domain-containing protein 3 (sTIM-3) were closely associated with the prognosis of patients. Soluble PD-L1 was negatively correlated with HGB and positively correlated with AST and NLR ( < 0.05). Soluble TIM-3 was negatively correlated with ALB and CD8+ T cells and positively correlated with HBV-DNA, AST, LDH and mTIM-3 expression in CD8+ T cells (<0.05).
We constructed a predictive model based on sICs to predict different survival times in HBV-HCC patients. The risk stratification effectively identified potentially critical patients. Soluble GITR, sPD-L1 and sTIM-3 were important immunological indicators which could dynamically monitor patients' immune status.
如今，免疫检查点阻断（ICB）疗法已成为肝细胞癌（HCC）免疫治疗的一个里程碑。然而，其临床疗效仍然较低。可溶性（s）免疫检查点（ICs）作为膜ICs的功能成分，是新型的生理性免疫调节剂。我们研究了sICs在乙型肝炎病毒相关性肝细胞癌（HBV-HCC）患者中的预后价值，并为未来免疫治疗的潜在新靶点提供临床线索。
本研究共纳入256名参与者。我们比较了健康对照（HC）、慢性乙型肝炎（CHB）、乙型肝炎相关肝硬化（HBV-LC）和HBV-HCC组中14种sICs的血浆水平。采用COX和随机生存森林（RSF）选择变量并构建模型，以预测HBV-HCC患者的总生存期。我们评估了预测效能，并分析了sICs、临床参数和膜ICs之间的相关性。
与HC相比，HBV-HCC中14种sICs的水平升高。RSF模型预测的1年、2年和3年生存期的受试者工作特征曲线下面积在训练集中分别为0.96、0.85和0.81，在验证集中分别为0.91、0.80和0.71。该模型可适应不同的事件分布和临床分期系统。可溶性糖皮质激素诱导的肿瘤坏死因子受体（sGITR）、可溶性程序性细胞死亡配体1（sPD-L1）和可溶性T细胞免疫球蛋白和含粘蛋白结构域蛋白3（sTIM-3）与患者的预后密切相关。可溶性PD-L1与血红蛋白呈负相关，与谷草转氨酶和中性粒细胞与淋巴细胞比值呈正相关（P<0.05）。可溶性TIM-3与白蛋白和CD8+T细胞呈负相关，与HBV-DNA、谷草转氨酶、乳酸脱氢酶以及CD8+T细胞中mTIM-3表达呈正相关（P<0.05）。
我们基于sICs构建了一个预测模型，以预测HBV-HCC患者的不同生存时间。风险分层有效地识别了潜在的关键患者。可溶性GITR、sPD-L1和sTIM-3是重要的免疫指标，可动态监测患者的免疫状态。
