Cell-targeted PD-1 agonists are potent NK-cell inhibitors
BackgroundThe programmed cell death protein 1 (PDCD1 or PD-1) is a key regulatory immune checkpoint and a major target for therapeutic intervention. In oncology, antibodies blocking the PD-1 pathway are used to activate immune cells to promote anti tumour immunity while in immune-mediated inflammato...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1640509/full |
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| author | Harriet C. Pope Harriet C. Pope Ana L. Chiodetti Alice Newey Guillaume Rieunier David X. Overton Eduardo Mateos-Diaz Tara M. Mahon Giovanna Bossi Hussein Al-Mossawi Charlotte Viant |
| author_facet | Harriet C. Pope Harriet C. Pope Ana L. Chiodetti Alice Newey Guillaume Rieunier David X. Overton Eduardo Mateos-Diaz Tara M. Mahon Giovanna Bossi Hussein Al-Mossawi Charlotte Viant |
| author_sort | Harriet C. Pope |
| collection | DOAJ |
| description | BackgroundThe programmed cell death protein 1 (PDCD1 or PD-1) is a key regulatory immune checkpoint and a major target for therapeutic intervention. In oncology, antibodies blocking the PD-1 pathway are used to activate immune cells to promote anti tumour immunity while in immune-mediated inflammatory diseases, PD-1 agonist molecules have the potential to achieve immune suppression. NK cells are a specialised population of innate lymphocytes able to recognize a large range of distressed cells including damaged tissues in autoimmune and inflammatory conditions. Of note, NK cells can upregulate PD-1 expression upon activation and their effector functions can be modulated by the PD-1 signalling pathway.MethodsWe have generated a novel bispecific inhibitory molecule, comprised of a targeting domain highly specific for a pre-pro-insulin peptide presented by the HLA-A*02 molecules on the cell surface of pancreatic β-cells and a PD-1 agonist effector domain. Suppressive effects of the β-cell tethered bispecific PD-1 agonist molecule on NK cells and NK92-PD-1 cell line activation were assessed through gene expression, cell surface expression of the CD107a degranulation marker, intracellular IFNγ production and Granzyme B secretion. EndoC-b cells proliferation and insulin production were also measured.ResultsWe observed that the bispecific PD-1 agonist molecules tethered to pancreatic b-cells accumulate at the immunological synapse, modify NK cell gene expression and decrease their inflammatory and cytotoxic functions.ConclusionsTargeted PD-1 agonist molecules, inhibiting T cells and NK cells in a tissue-specific manner offer a new promising treatment for autoimmune and inflammatory diseases. |
| format | Article |
| id | doaj-art-214cc5b00ee742fca4d78d34ac3eda8f |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-214cc5b00ee742fca4d78d34ac3eda8f2025-08-22T13:13:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16405091640509Cell-targeted PD-1 agonists are potent NK-cell inhibitorsHarriet C. Pope0Harriet C. Pope1Ana L. Chiodetti2Alice Newey3Guillaume Rieunier4David X. Overton5Eduardo Mateos-Diaz6Tara M. Mahon7Giovanna Bossi8Hussein Al-Mossawi9Charlotte Viant10Immunocore Ltd., Abingdon, United KingdomBath University, Bath, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomImmunocore Ltd., Abingdon, United KingdomBackgroundThe programmed cell death protein 1 (PDCD1 or PD-1) is a key regulatory immune checkpoint and a major target for therapeutic intervention. In oncology, antibodies blocking the PD-1 pathway are used to activate immune cells to promote anti tumour immunity while in immune-mediated inflammatory diseases, PD-1 agonist molecules have the potential to achieve immune suppression. NK cells are a specialised population of innate lymphocytes able to recognize a large range of distressed cells including damaged tissues in autoimmune and inflammatory conditions. Of note, NK cells can upregulate PD-1 expression upon activation and their effector functions can be modulated by the PD-1 signalling pathway.MethodsWe have generated a novel bispecific inhibitory molecule, comprised of a targeting domain highly specific for a pre-pro-insulin peptide presented by the HLA-A*02 molecules on the cell surface of pancreatic β-cells and a PD-1 agonist effector domain. Suppressive effects of the β-cell tethered bispecific PD-1 agonist molecule on NK cells and NK92-PD-1 cell line activation were assessed through gene expression, cell surface expression of the CD107a degranulation marker, intracellular IFNγ production and Granzyme B secretion. EndoC-b cells proliferation and insulin production were also measured.ResultsWe observed that the bispecific PD-1 agonist molecules tethered to pancreatic b-cells accumulate at the immunological synapse, modify NK cell gene expression and decrease their inflammatory and cytotoxic functions.ConclusionsTargeted PD-1 agonist molecules, inhibiting T cells and NK cells in a tissue-specific manner offer a new promising treatment for autoimmune and inflammatory diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1640509/fullcell-targeted PD-1 agonistsNK celltype 1 diabetesautoimmune diseasesNK cell inhibitionPD-1 pathway |
| spellingShingle | Harriet C. Pope Harriet C. Pope Ana L. Chiodetti Alice Newey Guillaume Rieunier David X. Overton Eduardo Mateos-Diaz Tara M. Mahon Giovanna Bossi Hussein Al-Mossawi Charlotte Viant Cell-targeted PD-1 agonists are potent NK-cell inhibitors Frontiers in Immunology cell-targeted PD-1 agonists NK cell type 1 diabetes autoimmune diseases NK cell inhibition PD-1 pathway |
| title | Cell-targeted PD-1 agonists are potent NK-cell inhibitors |
| title_full | Cell-targeted PD-1 agonists are potent NK-cell inhibitors |
| title_fullStr | Cell-targeted PD-1 agonists are potent NK-cell inhibitors |
| title_full_unstemmed | Cell-targeted PD-1 agonists are potent NK-cell inhibitors |
| title_short | Cell-targeted PD-1 agonists are potent NK-cell inhibitors |
| title_sort | cell targeted pd 1 agonists are potent nk cell inhibitors |
| topic | cell-targeted PD-1 agonists NK cell type 1 diabetes autoimmune diseases NK cell inhibition PD-1 pathway |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1640509/full |
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