Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection
BackgroundA 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/an...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.648420/full |
| _version_ | 1819136737498103808 |
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| author | Sara Ferrando-Martinez Angie Snell Bennett Elisabete Lino Adam J. Gehring Adam J. Gehring Jordan Feld Harry L. A. Janssen Scott H. Robbins |
| author_facet | Sara Ferrando-Martinez Angie Snell Bennett Elisabete Lino Adam J. Gehring Adam J. Gehring Jordan Feld Harry L. A. Janssen Scott H. Robbins |
| author_sort | Sara Ferrando-Martinez |
| collection | DOAJ |
| description | BackgroundA 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.MethodsHBV-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.ResultsThe 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.ConclusionHigher 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. |
| first_indexed | 2024-12-22T10:39:44Z |
| format | Article |
| id | doaj.art-1d3c2b542cb748e982935aa50d7154cf |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T10:39:44Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1d3c2b542cb748e982935aa50d7154cf2022-12-21T18:29:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-09-011210.3389/fimmu.2021.648420648420Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV InfectionSara Ferrando-Martinez0Angie Snell Bennett1Elisabete Lino2Adam J. Gehring3Adam J. Gehring4Jordan Feld5Harry L. A. Janssen6Scott H. Robbins7Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United StatesMicrobial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United StatesMicrobial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, United StatesToronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, CanadaDepartment of Immunology, University of Toronto, Toronto, ON, CanadaToronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, CanadaToronto Center for Liver Disease, Toronto General Hospital, University Health Network, Toronto, ON, CanadaLate Stage Oncology Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, United StatesBackgroundA 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.MethodsHBV-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.ResultsThe 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.ConclusionHigher 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.648420/fullchronic HBV infectionPD-L1 blockadeLAG3exhaustionHBV cure |
| spellingShingle | Sara Ferrando-Martinez Angie Snell Bennett Elisabete Lino Adam J. Gehring Adam J. Gehring Jordan Feld Harry L. A. Janssen Scott H. Robbins Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection Frontiers in Immunology chronic HBV infection PD-L1 blockade LAG3 exhaustion HBV cure |
| title | Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection |
| title_full | Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection |
| title_fullStr | Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection |
| title_full_unstemmed | Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection |
| title_short | Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection |
| title_sort | functional exhaustion of hbv specific cd8 t cells impedes pd l1 blockade efficacy in chronic hbv infection |
| topic | chronic HBV infection PD-L1 blockade LAG3 exhaustion HBV cure |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.648420/full |
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