Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function
Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and en...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-09-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S295032992400081X |
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| author | Luke Yi Hao Shalom Lerrer Matthieu Paiola Emily K. Moore Yevgeniya Gartshteyn Ruijiang Song Michael Goeckeritz Matilda J. Black Shoiab Bukhari Xizi Hu Adam Mor |
| author_facet | Luke Yi Hao Shalom Lerrer Matthieu Paiola Emily K. Moore Yevgeniya Gartshteyn Ruijiang Song Michael Goeckeritz Matilda J. Black Shoiab Bukhari Xizi Hu Adam Mor |
| author_sort | Luke Yi Hao |
| collection | DOAJ |
| description | Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and enhances anti-tumor T cell responses. This approach improves cancer patients’ outcomes. However, only one-third of the patients respond to these treatments. To better understand the mechanism of anti-PD-1 antibodies, we explored the location of PD-1 within the immune synapse. Surprisingly, we discovered that anti-PD-1 antibodies, besides blocking the interaction between PD-1 and its ligands, also removed PD-1 from the synapse. We demonstrated a correlation between removing PD-1 from the synapse by anti-PD-1 antibodies and the extent of T cell activation. Interestingly, a short version of the anti-PD-1 antibody, F(ab′)2, failed to remove PD-1 from the synapse and activate T cells. Using the syngeneic tumor model, we showed a superior anti-tumor effect of the anti-PD-1 antibody over the shorter version of the same antibody. Our data indicate that anti-PD-1 antibodies activate T cells by removing PD-1 from the synapse, and changing the location of PD-1 or other immune receptors within the immune synapse could serve as an alternative, efficient approach to treat cancer. |
| format | Article |
| id | doaj-art-0741c235bba34d5a89e9254a5a2bc2e7 |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-0741c235bba34d5a89e9254a5a2bc2e72025-08-20T02:22:16ZengElsevierMolecular Therapy: Oncology2950-32992024-09-0132320083910.1016/j.omton.2024.200839Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell functionLuke Yi Hao0Shalom Lerrer1Matthieu Paiola2Emily K. Moore3Yevgeniya Gartshteyn4Ruijiang Song5Michael Goeckeritz6Matilda J. Black7Shoiab Bukhari8Xizi Hu9Adam Mor10Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA; Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA; Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, 06108 Halle, GermanyColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA; Department of Medicine, Faculty of Biology, University of Cambridge, CB2 1TN Cambridge, UKColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USAColumbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA; Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Corresponding author: Adam Mor, Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032, USA.Targeting immune checkpoint receptors on T cells is a common cancer treatment strategy. Frequently, this is accomplished through antibodies targeting the ligand of inhibitory co-receptors. Blocking the immune checkpoint PD-1 binding to its ligands PD-L1 and PD-L2 prevents downstream signaling and enhances anti-tumor T cell responses. This approach improves cancer patients’ outcomes. However, only one-third of the patients respond to these treatments. To better understand the mechanism of anti-PD-1 antibodies, we explored the location of PD-1 within the immune synapse. Surprisingly, we discovered that anti-PD-1 antibodies, besides blocking the interaction between PD-1 and its ligands, also removed PD-1 from the synapse. We demonstrated a correlation between removing PD-1 from the synapse by anti-PD-1 antibodies and the extent of T cell activation. Interestingly, a short version of the anti-PD-1 antibody, F(ab′)2, failed to remove PD-1 from the synapse and activate T cells. Using the syngeneic tumor model, we showed a superior anti-tumor effect of the anti-PD-1 antibody over the shorter version of the same antibody. Our data indicate that anti-PD-1 antibodies activate T cells by removing PD-1 from the synapse, and changing the location of PD-1 or other immune receptors within the immune synapse could serve as an alternative, efficient approach to treat cancer.http://www.sciencedirect.com/science/article/pii/S295032992400081XMT: Regular Issueimmune synapset cellsmonoclonal antibodiescancer immunotherapyimmune checkpoints |
| spellingShingle | Luke Yi Hao Shalom Lerrer Matthieu Paiola Emily K. Moore Yevgeniya Gartshteyn Ruijiang Song Michael Goeckeritz Matilda J. Black Shoiab Bukhari Xizi Hu Adam Mor Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function Molecular Therapy: Oncology MT: Regular Issue immune synapse t cells monoclonal antibodies cancer immunotherapy immune checkpoints |
| title | Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function |
| title_full | Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function |
| title_fullStr | Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function |
| title_full_unstemmed | Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function |
| title_short | Exclusion of PD-1 from the immune synapse: A novel strategy to modulate T cell function |
| title_sort | exclusion of pd 1 from the immune synapse a novel strategy to modulate t cell function |
| topic | MT: Regular Issue immune synapse t cells monoclonal antibodies cancer immunotherapy immune checkpoints |
| url | http://www.sciencedirect.com/science/article/pii/S295032992400081X |
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