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A DNA Aptamer Targeting Galectin-1 as a Novel Immunotherapeutic Strategy for Lung Cancer
Yao-Tsung Tsai, Chen-Hsien Liang, Jin-Hsuan Yu, Kuan-Chih Huang, Chia-Hao Tung, Jia-En Wu, Yi-Ying Wu, Chih-Hsien Chang, Tse- Ming Hong, Yuh-Ling Chen Molecular Therapy - Nucleic Acids Volume 18, Pages (December 2019) DOI: /j.omtn Copyright © 2019 The Author(s) Terms and Conditions
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Molecular Therapy - Nucleic Acids 2019 18, 991-998DOI: (10. 1016/j
Molecular Therapy - Nucleic Acids , DOI: ( /j.omtn ) Copyright © 2019 The Author(s) Terms and Conditions
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Figure 1 AP-74 M-545, a Gal-1-Targeting Aptamer, Binds to the CRD of Gal-1 (A) Schematic illustration of His-tagged recombinant Gal-1 SELEX. (B) The dissociation constant of AP-74 M-545 was analyzed by using a nitrocellulose filter binding assay (n = 3) and calculated with GraphPad software. (C) The predicted secondary structure of AP-74 M-545. (D) The predicted 3D structure of AP-74 M-545 (top) and the docking simulation of AP-74 M-545 (light gray) with Gal-1 protein (red and gray) (bottom). The yellow arrow points to the CRD of the Gal-1 protein. Molecular Therapy - Nucleic Acids , DOI: ( /j.omtn ) Copyright © 2019 The Author(s) Terms and Conditions
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Figure 2 AP-74 M-545 Accumulates in Tumors and Suppresses Tumor Growth Only in LL/2 Lung Cancer C57BL/6 Murine Tumor Models (A) The dissociation constant of AP-74 M-545 to murine Gal-1 was analyzed by using a nitrocellulose filter binding assay (n = 3) and calculated with GraphPad software. (B) Biodistribution of the IRDye 800-scrambled aptamer or IRDye 800-AP-74 M-545 (1 μg) 6 h after intraperitoneal injection (n = 4 mice/group). (C) The scrambled aptamer (2 mg/kg, n = 5) or AP-74 M-545 (2 mg/kg, n = 5) was injected intratumorally. The data are presented as the mean ± SEM and were analyzed by Student’s t test. ∗P < 0.05, ∗∗P < 0.01. Molecular Therapy - Nucleic Acids , DOI: ( /j.omtn ) Copyright © 2019 The Author(s) Terms and Conditions
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Figure 3 Tumor-Infiltrating CD4 and CD8 T Cells Are Increased in AP-74 M-545-Treated Tumors Tumor-infiltrating CD4 and CD8 T cells were detected by immunochemistry staining. The data are presented as the mean ± SEM and were analyzed by Student’s t test. ∗P < 0.05, ∗∗P < 0.01. Molecular Therapy - Nucleic Acids , DOI: ( /j.omtn ) Copyright © 2019 The Author(s) Terms and Conditions
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Figure 4 AP-74 M-545 Blocks the Binding of Gal-1 to T Cells and Reduces the Gal-1-Mediated T Cell Apoptosis (A) AP-74 M-545 dose-dependently blocked the binding of FITC-Gal-1 (1 μM) to Jurkat T cells. Blue peak, T cell only; orange peak, Gal-1 FITC only; green peak, Gal-1 FITC + scrambled aptamer; red peak, Gal-1 FITC + AP-74 M-545. (B) AP-74 M-545 dose-dependently reduced Gal-1 (1.3 μM)-induced T cell apoptosis by annexin V (FL-1)-PI (FL-2) staining. The data are presented as the mean ± SEM and were analyzed by Student’s t test. ∗∗P < 0.01, ∗∗∗P < Molecular Therapy - Nucleic Acids , DOI: ( /j.omtn ) Copyright © 2019 The Author(s) Terms and Conditions
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Figure 5 AP-74 M-545 Blocks the Binding of Gal-1 to CD45 and Rescues IL-2 Expression (A) Ap-74 M-545 decreased the binding of Gal-1 to CD45. (B) T cell activation was detected by a T cell activation bioassay. (C) The expression level of IL-2 was increased in AP-74 M-545-treated tumor tissues from a murine model. The CD45 binding assay results are presented as the mean ± SEM and were analyzed by Student’s t test. ∗∗∗P < Molecular Therapy - Nucleic Acids , DOI: ( /j.omtn ) Copyright © 2019 The Author(s) Terms and Conditions
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