Ferrando-Martinez Sara, Huang Kelly, Bennett Angie Snell, Sterba Patricia, Yu Li, Suzich JoAnn A, Janssen Harry L A, Robbins Scott H
Microbial Sciences, AstraZeneca, Gaithersburg, MD, USA.
Statistical Sciences, AstraZeneca, Gaithersburg, MD, USA.
JHEP Rep. 2019 Jun 28;1(3):170-178. doi: 10.1016/j.jhepr.2019.06.001. eCollection 2019 Sep.
BACKGROUND & AIMS: Current therapies for chronic hepatitis B virus (HBV) infection control viral replication but do not eliminate the risk of progression to hepatocellular carcinoma. HBV-specific CD8 T cells are necessary for viral control, but they are rare and exhausted during chronic infection. Preclinical studies have shown that blockade of the PD-1:PD-L1 axis can restore HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status of patients impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.
Expression patterns of the PD-1:PD-L1/PD-L2 axis were analyzed in healthy donors and chronically infected patients in different clinical phases of disease. A functional assay was performed to quantify baseline HBV-specific T cell responses in chronically infected patients. Baseline responses were then compared to those attained in the presence of an anti-PD-L1 monoclonal antibody (MEDI2790).
Chronically infected patients were characterized by the upregulation of PD-1 within the T cell compartment and a concomitant upregulation of PD-L1 on myeloid dendritic cells. The upregulation was maximal in HBV e antigen (HBeAg)-positive patients but persisted after HBeAg negativization and was not restored by long-term treatment. HBV reactivity, measured as frequency of HBV-specific T cells, was significantly higher in HBeAg-negative patients with lower HBV DNA levels, independently of HBV surface antigen or alanine aminotransferase levels. Anti-PD-L1 blockade with MEDI2790 increased both the number of IFN-γ-producing T cells and the amount of IFN-γ produced per cell in 97% of patients with detectable HBV reactivity, independently of patients' clinical or treatment status.
Patients with lower levels of HBV DNA and the absence of HBeAg have more intact HBV-specific T cell immunity and may benefit the most from PD-L1 blockade as a monotherapy.
Hepatitis B virus (HBV)-specific T cell responses during chronic infection are weak due to the upregulation of inhibitor molecules on the immune cells. In this study we show that the inhibitory PD-1:PD-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not restore normal levels of PD-1 and PD-L1 expression. However, in HBV e antigen-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell responses by an average of 2-fold and is a promising new therapy for patients with chronic HBV infection.
目前慢性乙型肝炎病毒（HBV）感染的治疗方法可控制病毒复制，但不能消除进展为肝细胞癌的风险。HBV特异性CD8 T细胞对病毒控制至关重要，但在慢性感染期间数量稀少且功能耗竭。临床前研究表明，阻断PD-1:PD-L1轴可恢复HBV特异性T细胞功能。本研究旨在分析患者的临床和治疗状态如何影响HBV特异性T细胞对PD-L1阻断的反应能力。
分析健康供者以及处于疾病不同临床阶段的慢性感染患者中PD-1:PD-L1/PD-L2轴的表达模式。进行功能测定以量化慢性感染患者的基线HBV特异性T细胞反应。然后将基线反应与在抗PD-L1单克隆抗体（MEDI2790）存在下获得的反应进行比较。
慢性感染患者的特征是T细胞区室中PD-1上调，同时髓样树突状细胞上PD-L1上调。这种上调在乙肝e抗原（HBeAg）阳性患者中最为明显，但在HBeAg转阴后仍持续存在，且长期治疗后未恢复。以HBV特异性T细胞频率衡量的HBV反应性在HBV DNA水平较低的HBeAg阴性患者中显著更高，与HBV表面抗原或丙氨酸转氨酶水平无关。用MEDI2790进行抗PD-L1阻断可使97%具有可检测HBV反应性的患者中产生IFN-γ的T细胞数量和每个细胞产生的IFN-γ量均增加，与患者的临床或治疗状态无关。
HBV DNA水平较低且无HBeAg的患者具有更完整的HBV特异性T细胞免疫，作为单一疗法可能从PD-L1阻断中获益最大。
慢性感染期间，由于免疫细胞上抑制分子的上调，乙型肝炎病毒（HBV）特异性T细胞反应较弱。在本研究中，我们表明慢性HBV感染期间抑制性PD-1:PD-L1轴上调，成功的抗逆转录病毒治疗不能恢复PD-1和PD-L1表达的正常水平。然而，在HBeAg阴性患者中，用抗PD-L1抗体治疗可使HBV特异性T细胞反应功能平均增加2倍，是慢性HBV感染患者一种有前景的新疗法。
