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HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic Hepatitis B infection
Sara Ferrando-Martinez1, low asterisk, 'Correspondence information about the author Sara Ferrando-MartinezEmail the author Sara Ferrando-Martinez
, Kelly Huang1
, Angie Snell Bennett1
, Patricia Sterba1
, Li Yu2
, JoAnn A Suzich1
, Harry L.A. Janssen3
, Scott H. Robbins1
Open Access
DOI: https://doi.org/10.1016/j.jhepr.2019.06.001
Highlights
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Upregulation of the PD-1: PD-L1 axis is more profound in HBeAg-positive samples but does not normalize in HBeAg-negative or patients under antiviral therapy and successful viral suppression.
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HBV-specific T cell reactivity is higher in HBeAg-negative patients with low HBV DNA levels independently of ALT or HBsAg levels.
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97% of HBV-reactive patients respond to anti-PD-L1 blockade with MEDI2790 independent of their clinical status.
Abstract
Background and aims.
Current therapies for chronic 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 of the TPS functionality can be improved by HBV-specific T cell functionality. The aim of this study was to analyze how the clinical and treatment status impacts the ability of HBV-specific T cells to respond to PD-L1 blockade.
Methods
Expression patterns of the PD-1 D-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 a blocking anti-PD-L1 monoclonal antibody (MEDI2790).
Results
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 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 HBsAg or ALT levels. Anti-PD-L1 blockade with MEDI2790 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 their clinical and treatment status.
Conclusion
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.
LAY SUMMARY.
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 PD-1D-L1 axis is upregulated during chronic HBV infection and successful antiretroviral therapy does not The normal level of PD-1 and PD-L1 expression. However, in HBeAg-negative patients, treatment with an anti-PD-L1 antibody can increase the functionality of HBV-specific T cell response by an average of 2-fold and is a promising new therapy to treat patients with chronic HBV infection. |
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发表于 2019-7-19 13:59
