2. Academic Validation
  3. Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression

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

  • Biomaterials. 2020 Jul:247:119984. doi: 10.1016/j.biomaterials.2020.119984.
Smriti Gurung 1,  Fatima Khan 1,  Gowri Rangaswamy Gunassekaran 1,  Jae Do Yoo 1,  Sri Murugan Poongkavithai Vadevoo 1,  Uttapol Permpoon 1,  Sang-Hyun Kim 2,  Ha-Jeong Kim 3,  In-San Kim 4,  Hyeonjeong Han 5,  Ji-Ho Park 5,  Soyoun Kim 6,  Byungheon Lee 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
  • 2 Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
  • 3 Department of Physiology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
  • 4 Biomedical Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; KU-KIST School, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
  • 5 Department of Bio and Brain Engineering, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
  • 6 Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
  • 7 Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea. Electronic address: leebh@knu.ac.kr.
PMID: 32278214 DOI: 10.1016/j.biomaterials.2020.119984
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.

Keywords

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

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