Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression

Smriti Gurung, Fatima Khan, Gowri Rangaswamy Gunassekaran, Jae Do Yoo, Sri Murugan Poongkavithai Vadevoo, Uttapol Permpoon, Sang Hyun Kim, Ha Jeong Kim, In San Kim, Hyeonjeong Han, Ji Ho Park, Soyoun Kim, Byungheon Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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-L1Pep-1 and PD-L1Pep-2 preferentially bound to high PD-L1-expressing cells over low PD-L1-expressing cells; binding was further enhanced by interferon-γ, an inducer of PD-L1 expression. Binding affinities of PD-L1Pep-1 and PD-L1Pep-2 were approximately 373 and 281 nM, respectively. Cellular binding of the PD-L1-binding peptides was reduced by silencing PD-L1 gene expression or competition with anti-PD-L1 antibody. PD-L1Pep-1 and PD-L1Pep-2 induced the internalization and downregulated cell surface levels of PD-L1. 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-L1Pep-1 and PD-L1Pep-2 efficiently homed to tumor tissues, inhibited tumor growth, and increased CD8+/FoxP3+ ratio in mice. The PD-L1-binding peptides in combination with doxorubicin or PD-L1-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-L1Pep-2 block PD-L1 and reinvigorate T-cell activity, inhibiting tumor growth by enhancing anti-tumor immunity.

Original languageEnglish
Article number119984
JournalBiomaterials
Volume247
DOIs
Publication statusPublished - 2020 Jul

Keywords

  • Immune checkpoint blockade
  • PD-1
  • PD-L1
  • Peptides
  • Phage display
  • T-cell activity

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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  • Cite this

    Gurung, S., Khan, F., Gunassekaran, G. R., Yoo, J. D., Poongkavithai Vadevoo, S. M., Permpoon, U., Kim, S. H., Kim, H. J., Kim, I. S., Han, H., Park, J. H., Kim, S., & Lee, B. (2020). Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression. Biomaterials, 247, [119984]. https://doi.org/10.1016/j.biomaterials.2020.119984