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Peptide Blockers of PD-1-PD-L1 Interaction Reinvigorate PD-1-Suppressed T Cells and Curb Tumor Growth in Mice.
- Source :
-
Cells [Cells] 2024 Jul 15; Vol. 13 (14). Date of Electronic Publication: 2024 Jul 15. - Publication Year :
- 2024
-
Abstract
- The programmed cell death protein 1 (PD-1) plays a critical role in cancer immune evasion. Blocking the PD-1-PD-L1 interaction by monoclonal antibodies has shown remarkable clinical efficacy in treating certain types of cancer. However, antibodies are costly to produce, and antibody-based therapies can cause immune-related adverse events. To address the limitations associated with current PD-1/PD-L1 blockade immunotherapy, we aimed to develop peptide-based inhibitors of the PD-1/PD-L1 interaction as an alternative means to PD-1/PD-L1 blockade antibodies for anti-cancer immunotherapy. Through the functional screening of peptide arrays encompassing the ectodomains of PD-1 and PD-L1, followed by the optimization of the hit peptides for solubility and stability, we have identified a 16-mer peptide, named mL7N, with a remarkable efficacy in blocking the PD-1/PD-L1 interaction both in vitro and in vivo. The mL7N peptide effectively rejuvenated PD-1-suppressed T cells in multiple cellular systems designed to recapitulate the PD-1/PD-L1 interaction in the context of T-cell receptor signaling. Furthermore, PA-mL7N, a chimera of the mL7N peptide coupled to albumin-binding palmitic acid (PA), significantly promoted breast cancer cell killing by peripheral blood mononuclear cells ex vivo and significantly curbed tumor growth in a syngeneic mouse model of breast cancer. Our work raises the prospect that mL7N may serve as a prototype for the development of a new line of peptide-based immunomodulators targeting the PD-1/PD-L1 immune checkpoint with potential applications in cancer treatment.
- Subjects :
- Animals
Mice
Humans
Female
Cell Line, Tumor
Protein Binding drug effects
Cell Proliferation drug effects
Programmed Cell Death 1 Receptor metabolism
Programmed Cell Death 1 Receptor antagonists & inhibitors
B7-H1 Antigen metabolism
B7-H1 Antigen antagonists & inhibitors
Peptides pharmacology
Peptides chemistry
T-Lymphocytes immunology
T-Lymphocytes metabolism
T-Lymphocytes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2073-4409
- Volume :
- 13
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Cells
- Publication Type :
- Academic Journal
- Accession number :
- 39056775
- Full Text :
- https://doi.org/10.3390/cells13141193