A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects
Journal
Molecular Therapy - Nucleic Acids
Journal Volume
5
Pages
e397
Date Issued
2016
Author(s)
Abstract
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. ? 2016 Official journal of the American Society of Gene & Cell Therapy
Subjects
aptamer; immunotherapy; PD-1; PD-L1; tumor microenvironment
SDGs
Other Subjects
alpha chemokine; aptamer; atezolizumab; CD31 antigen; chemokine receptor CXCR3; CXCL9 chemokine; gamma interferon; gamma interferon inducible protein 10; interleukin 2; programmed death 1 ligand 1; tumor necrosis factor; A-549 cell line; animal experiment; animal model; antineoplastic activity; Article; cancer immunotherapy; cancer inhibition; CD4+ T lymphocyte; CD8+ T lymphocyte; controlled study; hop92 cancer cell line; human; human cell; in vitro study; liver toxicity; lung cancer cell line; lymphocyte proliferation; molecular docking; mouse; nephrotoxicity; nonhuman; priority journal; protein expression; protein protein interaction; protein targeting; sequence alignment; tumor growth; tumor microenvironment; tumor volume
Publisher
Elsevier Inc
Type
journal article