title: 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.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cherryholmes
authors.forename: Wang
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Christoph
authors.initials: C
authors.lastname: Lahtz
authors.forename: Claudia
authors.initials: C
authors.lastname: Kowolik
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000235:genetics*; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D052157:Aptamers, Nucleotide; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse