Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF | Corrigendum
Technical Advance Article has an altmetric score of 28

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

  • Text
  • PDF
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

×

Figure 7

Treating human T cell lymphoma with CTLA4apt–STAT3 siRNA inhibits tumor growth.

Options: View larger image (or click on image) Download as PowerPoint
Treating human T cell lymphoma with CTLA4apt–STAT3 siRNA inhibits tumor ...
(A) Human T cell lymphoma tissue array was stained for CTLA4 expression and analyzed by direct immunofluorescence and (B) quantified (all n = 3). Magnified areas (dashed line) are shown in the lower left corner. Scale bar: 100 μm. Insets were generated in silico by a digital zoom of the indicated regions of interest. SD is shown. **P < 0.01; ***P < 0.001, t test. (C) Tumor growth kinetics of Karpas299 T cell lymphoma engrafted into athymic nude mice treated every other day with CTLA4apt–STAT3 siRNA, CTLA4apt–LUC siRNA, or vehicle. (D) Flow cytometry showing phospho-STAT3 expression and apoptotic cell death in the human T cell lymphoma tumors treated as indicated. (E) Human T cell lymphoma tumor microsections prepared from mice treated as indicated were stained for Ki67+ proliferative activity (upper panels), CD31+ tumor vasculature (middle panels), and B7-H1+ (lower panels). Scale bars: 100 μm. Fluorescent signals of Ki67 (n = 5) and B7-H1 (n = 4), and CD31+ (n = 5) blood vessel length assessed by confocal microscopy were quantified from independent fields of view; bar graph shows CTLA4apt–STAT3 siRNA (light gray), CTLA4apt–LUC siRNA (dark gray), or vehicle (PBS, black). SD is shown. **P < 0.01; ***P < 0.001, 2 tailed Student’s t test.

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

Sign up for email alerts

Picked up by 2 news outlets
Blogged by 1
Referenced in 10 patents
120 readers on Mendeley
See more details