Journal
BIOMATERIALS
Volume 247, Issue -, Pages -Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2020.119984
Keywords
Immune checkpoint blockade; PD-1; PD-L1; Peptides; Phage display; T-cell activity
Funding
- National Research Foundation [NRF-2014R1A5A2009242, NRF-2018R1A2B2008378]
- Bio & Medical Technology Development Program - Ministry of Science ICT of Korea [2017M3A9G8083382]
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Blockade of programmed cell death ligand-1 (PD-L1) restores T-cell activity and enhances anti-tumor immunity. Screening a phage-displayed peptide library for peptides that selectively bind to PD-L1-overexpressing cells identified two peptides, CLQKTPKQC and CVRARTR (PD-L1Pep-1 and PD-L1Pep-2, respectively) that appeared to block PD-L1. PD-L1 Pep-1 and PD-L1 Pep-2 preferentially bound to high PD-L1 -expressing cells over low PD-L1-expressing cells; binding was further enhanced by interferon-gamma, an inducer of PD-L1 expression. Binding affinities of PD-L1 Pep-1 and PD-L1 Pep-2 were approximately 373 and 281 nM, respectively. Cellular binding of the PD-L1-binding peptides was reduced by silencing PD-Ll gene expression or competition with anti-PD-Ll antibody. PD-L1 Pep-1 and PD-L1 Pep-2 induced the internalization and downregulated cell surface levels of PD-Ll. The PD-L1-binding peptides restored cytokine secretion and T-cell proliferation to cells inhibited by co-culture with tumor cells or culture on PD-L1-coated plates. Intravenously injected PD-L1 Pep-1 and PD-L1 Pep-2 efficiently homed to tumor tissues, inhibited tumor growth, and increased CD8 + /FoxP3 + ratio in mice. The PD-Ll -binding peptides in combination with doxorubicin or PD-Ll -targeted liposomal doxorubicin inhibited tumor growth and increased CD8 + /FoxP3 + ratio more efficiently than doxorubicin alone and untargeted liposomal doxorubicin, respectively. These results suggest that PD-L1Pep-1 and PD-L1 Pep-2 block PD-Ll and reinvigorate T-cell activity, inhibiting tumor growth by enhancing anti-tumor immunity.
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