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CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells
Andreas Herrmann, … , Marcin Kortylewski, Hua Yu
Andreas Herrmann, … , Marcin Kortylewski, Hua Yu
Published June 2, 2014
Citation Information: J Clin Invest. 2014;124(7):2977-2987. https://doi.org/10.1172/JCI73174.
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Technical Advance Article has an altmetric score of 28

CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells

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Abstract

Intracellular therapeutic targets that define tumor immunosuppression in both tumor cells and T cells remain intractable. Here, we have shown that administration of a covalently linked siRNA to an aptamer (apt) that selectively binds cytotoxic T lymphocyte–associated antigen 4 (CTLA4apt) allows gene silencing in exhausted CD8+ T cells and Tregs in tumors as well as CTLA4-expressing malignant T cells. CTLA4 expression was upregulated in CD8+ T cells in the tumor milieu; therefore, CTLA4apt fused to a STAT3-targeting siRNA (CTLA4apt–STAT3 siRNA) resulted in internalization into tumor-associated CD8+ T cells and silencing of STAT3, which activated tumor antigen–specific T cells in murine models. Both local and systemic administration of CTLA4apt–STAT3 siRNA dramatically reduced tumor-associated Tregs. Furthermore, CTLA4apt–STAT3 siRNA potently inhibited tumor growth and metastasis in various mouse tumor models. Importantly, CTLA4 expression is observed in T cells of patients with blood malignancies, and CTLA4apt–STAT3 siRNA treatment of immunodeficient mice bearing human T cell lymphomas promoted tumor cell apoptosis and tumor growth inhibition. These data demonstrate that a CTLA4apt-based siRNA delivery strategy allows gene silencing in both tumor-associated T cells and tumor cells and inhibits tumor growth and metastasis.

Authors

Andreas Herrmann, Saul J. Priceman, Maciej Kujawski, Hong Xin, Gregory A. Cherryholmes, Wang Zhang, Chunyan Zhang, Christoph Lahtz, Claudia Kowolik, Steve J. Forman, Marcin Kortylewski, Hua Yu

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Figure 6

In vivo delivery of CTLA4apt conjugate into CTLA4+ human T cell lymphoma.

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In vivo delivery of CTLA4apt conjugate into CTLA4+ human T cell lymphoma...
(A) CTLA4 expression by Karpas299 human T cell lymphoma was assessed by flow cytometry. (B) CTLA4apt at 500 pmol/ml and CTLA4 protein were analyzed for colocalization in Karpas299 T cell lymphoma cells by confocal microscopy in indicated time kinetics. Scale bars: 10 μm. (C) Flow cytometry showing that uptake of the aptamer-siRNA conjugate is more efficient in CTLA4+ human T cell lymphoma Karpas cells for 2 hours with 500 pmol/ml CTLA4-apt–STAT3 siRNA. Gating on CTLA4+ Karpas cells positive for CTLA4apt–STAT3 siRNA-FITC (upper right quadrant). (D) Flow cytometry analysis showing uptake kinetics of fluorescent CTLA4apt–STAT3 siRNA by human Karpas299 T cell lymphoma at indicated doses and time points in vitro. Gating on Karpas cells positive for CTLA4apt–STAT3 siRNA-FITC. (E) Efficacy of in vivo silencing targeting luciferase. Luciferase+ Karpas299 tumors engrafted s.c. in immunocompromised mice were treated 3 times every other day with CTLA4apt–LUC siRNA or CTLA4apt as a control. Bioluminescent noninvasive imaging was performed at time points as indicated, and luminescent signal was quantified (right panel). SD is shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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