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Background  A functional cure for chronic HBV could be achieved by boosting HBV-specific immunity.  In vitro  studies show that immunotherapy could be an effective strategy. However, these studies include strategies to enrich HBV-specific CD8 T cells, which could alter the expression of the anti-PD-1/anti-PD-L1 antibody targets. Our aim was to determine the efficacy of PD-L1 blockade  ex vivo .    Methods  HBV-specific CD8 T cells were characterized  ex vivo  by flow cytometry for the simultaneous analysis of six immune populations and 14 activating and inhibitory receptors.  Ex vivo  functionality was quantified by ELISpot and by combining peptide pool stimulation, dextramers and intracellular flow cytometry staining.    Results  The functionality of HBV-specific CD8 T cells is associated with a higher frequency of cells with low exhaustion phenotype (LAG3 - TIM3 - PD-1 + ), independently of the clinical parameters. The accumulation of HBV-specific CD8 T cells with a functionally exhausted phenotype (LAG3 + TIM3 + PD-1 + ) is associated with lack of  ex vivo  functionality. PD-L1 blockade enhanced the HBV-specific CD8 T cell response only in patients with lower exhaustion levels, while response to PD-L1 blockade was abrogated in patients with higher frequencies of exhausted HBV-specific CD8 T cells.    Conclusion  Higher levels of functionally exhausted HBV-specific CD8 T cells are associated with a lack of response that cannot be restored by blocking the PD-1:PD-L1 axis. This suggests that the clinical effectiveness of blocking the PD-1:PD-L1 axis as a monotherapy may be restricted. Combination strategies, potentially including the combination of anti-LAG-3 with other anti-iR antibodies, will likely be required to elicit a functional cure for patients with high levels of functionally exhausted HBV-specific CD8 T cells.

Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection