A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects
The PD-1/PD-L1 axis is a major pathway involved in tumor immune evasion. Here, we report the novel PD-L1 antagonizing DNA aptamer (aptPD-L1) and demonstrate an integrated pipeline that expedites therapeutic aptamer development. Aptamer can exert antibody-mimic functions and is advantageous over anti...
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doaj-fdd4a745bd504e748679bbd077db2db82020-11-24T22:55:22ZengElsevierMolecular Therapy: Nucleic Acids2162-25312016-01-015C10.1038/mtna.2016.102A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor EffectsWei-Yun Lai0Bo-Tsang Huang1Jen-Wei Wang2Pei-Ying Lin3Pan-Chyr Yang4Aptamer Core Facility, Institute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanAptamer Core Facility, Institute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanThe PD-1/PD-L1 axis is a major pathway involved in tumor immune evasion. Here, we report the novel PD-L1 antagonizing DNA aptamer (aptPD-L1) and demonstrate an integrated pipeline that expedites therapeutic aptamer development. Aptamer can exert antibody-mimic functions and is advantageous over antibody for its chemically synthetic nature, low immunogenicity, and efficient tissue penetration. Our results showed that aptPD-L1 blocked the binding between human PD-1 and PD-L1. Experiments using murine models showed that aptPD-L1 promoted in vitro lymphocyte proliferation and suppressed in vivo tumor growth without the induction of observable liver or renal toxicity. Analyses on the aptPD-L1-treated tumors further revealed elevated levels of infiltrating CD4+ and CD8+ T cells, intratumoral IL-2, TNF-α, interferon (IFN)-γ and the C-X-C motif chemokines, CXCL9 and CXCL10. The CD8+ T cells in the aptPD-L1-treated tumors had higher CXCR3 expression level compared to the random-sequence oligonucleotides-treated ones. Besides, the length and density of CD31+ intratumoral microvessels were significantly decreased in the aptPD-L1 treatment group. Collectively, our data suggested that aptPD-L1 helps T cell function restoration and modifies tumor microenvironment. These chemokines might orchestrate together to attract more T cells into the tumor tissues to form the positive amplification loop against tumor growth, indicating the translational potential of aptPD-L1 in cancer immunotherapy.http://www.sciencedirect.com/science/article/pii/S2162253117300185aptamerimmunotherapyPD-1PD-L1tumor microenvironment |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei-Yun Lai Bo-Tsang Huang Jen-Wei Wang Pei-Ying Lin Pan-Chyr Yang |
spellingShingle |
Wei-Yun Lai Bo-Tsang Huang Jen-Wei Wang Pei-Ying Lin Pan-Chyr Yang A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects Molecular Therapy: Nucleic Acids aptamer immunotherapy PD-1 PD-L1 tumor microenvironment |
author_facet |
Wei-Yun Lai Bo-Tsang Huang Jen-Wei Wang Pei-Ying Lin Pan-Chyr Yang |
author_sort |
Wei-Yun Lai |
title |
A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects |
title_short |
A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects |
title_full |
A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects |
title_fullStr |
A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects |
title_full_unstemmed |
A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects |
title_sort |
novel pd-l1-targeting antagonistic dna aptamer with antitumor effects |
publisher |
Elsevier |
series |
Molecular Therapy: Nucleic Acids |
issn |
2162-2531 |
publishDate |
2016-01-01 |
description |
The PD-1/PD-L1 axis is a major pathway involved in tumor immune evasion. Here, we report the novel PD-L1 antagonizing DNA aptamer (aptPD-L1) and demonstrate an integrated pipeline that expedites therapeutic aptamer development. Aptamer can exert antibody-mimic functions and is advantageous over antibody for its chemically synthetic nature, low immunogenicity, and efficient tissue penetration. Our results showed that aptPD-L1 blocked the binding between human PD-1 and PD-L1. Experiments using murine models showed that aptPD-L1 promoted in vitro lymphocyte proliferation and suppressed in vivo tumor growth without the induction of observable liver or renal toxicity. Analyses on the aptPD-L1-treated tumors further revealed elevated levels of infiltrating CD4+ and CD8+ T cells, intratumoral IL-2, TNF-α, interferon (IFN)-γ and the C-X-C motif chemokines, CXCL9 and CXCL10. The CD8+ T cells in the aptPD-L1-treated tumors had higher CXCR3 expression level compared to the random-sequence oligonucleotides-treated ones. Besides, the length and density of CD31+ intratumoral microvessels were significantly decreased in the aptPD-L1 treatment group. Collectively, our data suggested that aptPD-L1 helps T cell function restoration and modifies tumor microenvironment. These chemokines might orchestrate together to attract more T cells into the tumor tissues to form the positive amplification loop against tumor growth, indicating the translational potential of aptPD-L1 in cancer immunotherapy. |
topic |
aptamer immunotherapy PD-1 PD-L1 tumor microenvironment |
url |
http://www.sciencedirect.com/science/article/pii/S2162253117300185 |
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