Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection
| العنوان: | Functional Exhaustion of HBV-Specific CD8 T Cells Impedes PD-L1 Blockade Efficacy in Chronic HBV Infection |
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| المؤلفون: | Sara Ferrando-Martinez, Harry L.A. Janssen, Elisabete Lino, Adam J. Gehring, Scott H. Robbins, Angie Snell Bennett, Jordan J. Feld |
| المصدر: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| بيانات النشر: | Frontiers Media S.A., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, Hepatitis B virus, LAG3, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Immunology, CD8-Positive T-Lymphocytes, PD-L1 blockade, B7-H1 Antigen, Cohort Studies, Immune system, Hepatitis B, Chronic, Antigens, CD, exhaustion, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, Immune Checkpoint Inhibitors, Original Research, HBV cure, biology, business.industry, ELISPOT, chronic HBV infection, Immunotherapy, Middle Aged, RC581-607, Lymphocyte Activation Gene 3 Protein, Blockade, biology.protein, Cancer research, Female, Antibody, Immunologic diseases. Allergy, business, Ex vivo |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1664-3224 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d229091d192f5f4f56fbc6781da47ac1Test https://www.frontiersin.org/articles/10.3389/fimmu.2021.648420/fullTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d229091d192f5f4f56fbc6781da47ac1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16643224 |
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