B型肝炎病毒帶原者之血漿Programmed Cell Death-1蛋白濃度與肝細胞癌之前瞻性探討

Abstract

背景與目的：慢性B型肝炎病毒感染會導致T細胞衰竭和肝細胞癌。PD-1是一種抑制接受器在慢性B型肝炎病毒感染期間參與T細胞失能，並降低對抗癌症的免疫反應。本研究透過一項B型肝炎病毒帶原者的世代研究，調查可溶性PD-1（sPD-1）與肝細胞癌的關係，以及調查已知的肝細胞癌危險因子是否與可溶性sPD-1存在可能的交互作用，危險因子包含會損壞免疫反應的過量BMI與吸菸習慣。 材料與方法：於1989至1992年間總共徵募2905位30歲以上男性B型肝炎帶原者，追蹤至2010年底。每位個案剛進研究時採集血液樣本，並使用結構式問卷收集社會人口學、生活習慣與醫療史資料。個案固定每年進行追蹤，若罹患肝細胞癌時會更頻繁追蹤。透過ELISA測量研究起點的血漿樣本得到sPD-1濃度。使用已調整的Cox 比例風險迴歸模型估算危險因子與肝細胞癌之間的關係。 結果：肝細胞癌累積發生率隨sPD-1四分位數分層上升而增加（P=0.0004）。經調整年齡、教育、籍貫、ALT、肝細胞癌家族史、有無慢性肝炎或肝硬化、以及菸包年數後，血漿sPD-1與肝細胞癌的風險有正相關，在最高sPD-1四分位數分層的風險比為2.5（95%信賴區間：1.54－4.06）。香菸包年數（P<0.0001）和BMI（P<0.0001）與血漿sPD-1之間有負相關。然而，上述兩個危險因子對於血漿sPD-1與肝細胞癌的關係沒有顯著影響或改變。 結論：我們發現血漿sPD-1與B型肝炎病毒健康帶原者進展成HCC患者之過程有顯著相關。吸菸或肥胖對於sPD-1濃度皆無發現明顯交互作用。

Background and Aims: Chronic HBV infection can lead to T cell exhaustion and hepatocellular carcinoma (HCC). Programmed cell death-1 (PD-1) is an inhibitory receptor involved in T-cell dysfunction during chronic HBV infection, and diminished antitumor immune responses. Using a cohort study of HBV carriers, this study aimed to investigate the association between plasma levels of soluble PD-1 (sPD-1) and HCC, and determine whether there might be interactions of sPD-1 levels with known HCC risk factors, including excess body mass index (BMI) and smoking, which impair immune response. Materials and Methods: A total of 2905 male HBV carriers aged ≥30 years old were enrolled between 1989 and 1992, and followed up to the end of 2010. At baseline, data on sociodemographic characteristics, lifestyle habits, and medical history were collected from structured questionnaire, and blood sample was collected from each participant. Subjects were invited for follow-up every year and more frequently if indicated HCC. sPD-1 levels were determined by using baseline plasma levels with ELISA. Adjusted Cox proportional hazards regression models are used to evaluate the association between risk factors and HCC. Result: Cumulative incidence of HCC increased with increasing quartile levels of sPD-1 (P=0.0004). There was a positive association between plasma sPD-1 and the risk of HCC, showing the hazard ratio of 2.5 (95% confidence interval: 1.54 to 4.06) in the highest quartile level of plasma sPD-1, after adjustment for age, education, ancestral home, ALT, family history of HCC, chronic hepatitis and liver cirrhosis. Pack-years of cigarette smoking (P <0.0001) and BMI (P <0.0001) were inversely correlated with plasma sPD-1 levels. However, there was no significant effect modification by either of the two factors observed on the association between plasma sPD-1 and HCC. Conclusion: We found a significant association between plasma sPD-1 and transition from healthy HBV carrier state to HCC. No notable interaction with sPD-1 levels was found for either smoking or obesity.