期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 7, 页码 2977-2987出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73174
关键词
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资金
- V Foundation
- Billy and Audrey L. Wilder Endowment
- National Cancer Institute of the NIH [P30CA033572]
- [R01CAl22976]
- [R01CA146092]
- [P50 CA107399]
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.
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