Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
Sci Rep. 2022 Jan 7;12(1):105. doi: 10.1038/s41598-021-03706-w.
Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.
可溶性免疫检查点分子是新兴的免疫调节介质。然而，尚不清楚可溶性免疫检查点蛋白是否会影响慢性乙型肝炎病毒感染患者接受核苷（酸）类似物（NA）治疗期间肝细胞癌（HCC）的发展。本研究纳入了 122 例初治 NA 的患者，评估了包括可溶性免疫检查点蛋白在内的临床因素与 NA 治疗期间 HCC 发展的相关性。采用基于多重荧光珠的免疫分析方法检测了 16 种可溶性免疫检查点蛋白的基线血清浓度。在随访期间（中位时间 4.3 年），共有 13 例患者发生 HCC。在 16 种蛋白中，可溶性诱导型 T 细胞共刺激物（≥164.71pg/ml；p=0.014）、可溶性程序性死亡-1（sPD-1）（≤447.27pg/ml；p=0.031）、可溶性 CD40（≤493.68pg/ml；p=0.032）和可溶性疱疹病毒进入介质（≤2470.83pg/ml；p=0.038）与 HCC 发展显著相关（对数秩检验）。多变量分析显示，sPD-1 水平≤447.27pg/ml（p=0.014；危险比 [HR]，4.537）和 AFP 水平≥6.4ng/ml（p=0.040；HR，5.524）与 HCC 发展独立且显著相关。治疗前 sPD-1 是预测 NA 治疗期间 HCC 发展的新型预测生物标志物。
