title: Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia.
abstract: Targeting oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) in acute myeloid leukemia (AML) can reduce blast survival and tumor immune evasion. Decoy oligodeoxynucleotides (dODNs), which comprise STAT3-specific DNA sequences are competitive inhibition of STAT3 transcriptional activity. To deliver STAT3dODN specifically to myeloid cells, we linked STAT3dODN to the Toll-like receptor 9 (TLR9) ligand, cytosine guanine dinucleotide (CpG). The CpG-STAT3dODN conjugates are quickly internalized by human and mouse TLR9(+)immune cells (dendritic cells, B cells) and the majority of patients' derived AML blasts, including leukemia stem/progenitor cells. Following uptake, CpG-STAT3dODNs are released from endosomes, and bind and sequester cytoplasmic STAT3, thereby inhibiting downstream gene expression in target cells. STAT3 inhibition in patients' AML cells limits their immunosuppressive potential by reduced arginase expression, thereby partly restoring T-cell proliferation. Partly chemically modified CpG-STAT3dODNs have >60 hours serum half-life which allows for IV administration to leukemia-bearing mice (50% effective dose ∼ 2.5 mg/kg). Repeated administration of CpG-STAT3dODN resulted in regression of human MV4-11 AML in mice. The antitumor efficacy of this strategy is further enhanced in immunocompetent mice by combining direct leukemia-specific cytotoxicity with immunogenic effects of STAT3 blocking/TLR9 triggering. CpG-STAT3dODN effectively reducedCbfb/MYH11/MplAML burden in various organs and eliminated leukemia stem/progenitor cells, mainly through CD8/CD4 T-cell-mediated immune responses. In contrast, small-molecule Janus kinase 2/STAT3 inhibitor failed to reproduce therapeutic effects of cell-selective CpG-STAT3dODN strategy. These results demonstrate therapeutic potential of CpG-STAT3dODN inhibitors with broad implications for treatment of AML and potentially other hematologic malignancies.
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA; Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, People's Republic of China;
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Dewan Md Sakib
authors.initials: DM
authors.lastname: Hossain
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Priyanka
authors.initials: P
authors.lastname: Duttagupta
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Dayson
authors.initials: D
authors.lastname: Moreira
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Xingli
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Haejung
authors.initials: H
authors.lastname: Won
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Sergey
authors.initials: S
authors.lastname: Nechaev
authors.affiliation: Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland;
authors.forename: Marcin
authors.initials: M
authors.lastname: Majka
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope, Duarte, CA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA; and.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.affiliation: DNA/RNA Synthesis Core Facility, Beckman Research Institute at City of Hope, Duarte, CA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope, Duarte, CA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA; and.
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute at City of Hope, Duarte, CA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA; and.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA;
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D018899:CpG Islands; D004355:Drug Stability; D018816:Genes, cdc / Q000187:drug effects* / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D044967:Serum / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D019139:Tumor Escape / Q000187:drug effects*
chemical_list: D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor