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

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 (CTLA4(apt)) 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, CTLA4(apt) fused to a STAT3-targeting siRNA (CTLA4(apt)-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 CTLA4(apt)-STAT3 siRNA dramatically reduced tumor-associated Tregs. Furthermore, CTLA4(apt)-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 CTLA4(apt)-STAT3 siRNA treatment of immunodeficient mice bearing human T cell lymphomas promoted tumor cell apoptosis and tumor growth inhibition. These data demonstrate that a CTLA4(apt)-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, Piotr Swiderski, Maciej Kujawski, Hong Xin, Gregory A Cherryholmes, Wang Zhang, Chunyan Zhang, Christoph Lahtz, Claudia Kowolik, Steve J Forman, Marcin Kortylewski, Hua Yu
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 7 Pg. 2977-87 (Jul 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24892807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aptamers, Nucleotide
• CTLA-4 Antigen
• CTLA4 protein, human
• Ctla4 protein, mouse
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• Stat3 protein, mouse

Topics

• Animals
• Aptamers, Nucleotide (administration & dosage, genetics)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• CTLA-4 Antigen (genetics)
• Cell Line, Tumor
• Gene Silencing
• Humans
• Immunotherapy, Adoptive (methods)
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Lymphoma, T-Cell (immunology, therapy)
• Melanoma, Experimental (immunology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• RNA, Small Interfering (administration & dosage, genetics)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics)
• T-Lymphocytes, Regulatory (immunology, metabolism)