Article ; Online: Identification of the functional PD-L1 interface region responsible for PD-1 binding and initiation of PD-1 signaling.
The Journal of biological chemistry
2023 Volume 299, Issue 12, Page(s) 105353
Abstract: The PD-1/PD-L1 checkpoint pathway is important for regulating immune responses and can be targeted by immunomodulatory drugs to treat a variety of immune disorders. However, the precise protein-protein interactions required for the initiation of PD-1/PD- ... ...
| Abstract | The PD-1/PD-L1 checkpoint pathway is important for regulating immune responses and can be targeted by immunomodulatory drugs to treat a variety of immune disorders. However, the precise protein-protein interactions required for the initiation of PD-1/PD-L1 signaling are currently unknown. Previously, we designed a series of first-generation PD-1 targeting peptides based on the native interface region of programmed death ligand 1 (PD-L1) that effectively reduced PD-1/PD-L1 binding. In this work, we further characterized the previously identified lead peptide, MN1.1, to identify key PD-1 binding residues and design an optimized peptide, MN1.4. We show MN1.4 is significantly more stable than MN1.1 in serum and retains the ability to block PD-1/PD-L1 complex formation. We further characterized the immunomodulatory effects of MN1.4 treatment by measuring markers of T cell activation in a co-culture model with ovarian cancer cells and peripheral blood mononuclear cells. We found MN1.4 treatment reduced cytokine secretion and suppressed T cell responses in a similar manner as recombinant PD-L1. Therefore, the PD-L1 interface region used to design MN1.4 appeared sufficient to initiate PD-1 signaling and likely represents the minimum necessary region of PD-L1 required for PD-1 recognition. We propose a peptide agonist for PD-1, such as MN1.4, could have several applications for treating autoimmune disorders caused by PD-1 deficiencies such as type 1 diabetes, inflammatory arthritis, or autoimmune side effects arising from monoclonal antibody-based cancer immunotherapies. |
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| MeSH term(s) | Humans ; B7-H1 Antigen/chemistry ; B7-H1 Antigen/genetics ; B7-H1 Antigen/metabolism ; Immunotherapy ; Leukocytes, Mononuclear/metabolism ; Neoplasms/drug therapy ; Peptides/pharmacology ; Programmed Cell Death 1 Receptor/agonists ; Programmed Cell Death 1 Receptor/chemistry ; Programmed Cell Death 1 Receptor/metabolism ; Protein Binding ; Signal Transduction ; Mutation ; Models, Molecular ; Protein Structure, Quaternary ; Cell Line, Tumor ; Immunity/drug effects |
| Chemical Substances | B7-H1 Antigen ; Peptides ; Programmed Cell Death 1 Receptor |
| Language | English |
| Publishing date | 2023-10-17 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2997-x |
| ISSN | 1083-351X ; 0021-9258 |
| ISSN (online) | 1083-351X |
| ISSN | 0021-9258 |
| DOI | 10.1016/j.jbc.2023.105353 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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