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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.
Insights
A novel aptamer-siRNA conjugate targets cytotoxic T lymphocyte-associated antigen 4 (CTLA4) to silence STAT3 in tumor cells and T cells. This approach inhibits tumor growth and metastasis by reactivating anti-tumor immunity.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Intracellular targets for tumor immunosuppression in tumor and T cells are challenging to address.
- Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is upregulated in tumor-infiltrating CD8+ T cells.
Purpose of the Study:
- To develop a novel delivery strategy for gene silencing in tumor cells and T cells.
- To investigate the efficacy of CTLA4-targeted siRNA against STAT3 in preclinical cancer models.
Main Methods:
- Conjugation of a CTLA4-specific aptamer with a STAT3-targeting siRNA (CTLA4(apt)-STAT3 siRNA).
- Administration of CTLA4(apt)-STAT3 siRNA in murine tumor models and in immunodeficient mice bearing human T cell lymphomas.
- Assessment of gene silencing, immune cell activation, tumor growth, and metastasis.
Main Results:
- CTLA4(apt)-STAT3 siRNA effectively silenced STAT3 in tumor-associated CD8+ T cells and Tregs.
- Treatment reduced tumor-associated Tregs and activated tumor antigen-specific T cells.
- Significant inhibition of tumor growth and metastasis was observed in various mouse models.
- CTLA4(apt)-STAT3 siRNA promoted apoptosis and inhibited tumor growth in human T cell lymphoma xenografts.
Conclusions:
- A CTLA4-aptamer based siRNA delivery system enables gene silencing in both tumor-infiltrating T cells and malignant T cells.
- This strategy holds promise for treating CTLA4-expressing malignancies by overcoming tumor immunosuppression.
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