title: Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity.
abstract: Signal transducer and activator of transcription 3 (STAT3) is an oncogene and immune checkpoint commonly activated in cancer cells and in tumor-associated immune cells. We previously developed an immunostimulatory strategy based on targeted Stat3 silencing in Toll-like receptor 9 (TLR9)-positive hematopoietic cells using CpG-small interfering RNA (siRNA) conjugates. Here, we assessed the therapeutic effect of systemic STAT3 blocking/TLR9 triggering in disseminated acute myeloid leukemia (AML). We used mouse Cbfb-MYH11/Mpl-induced leukemia model, which mimics human inv(16) AML. Our results demonstrate that intravenously delivered CpG-Stat3 siRNA, but not control oligonucleotides, can eradicate established AML and impair leukemia-initiating potential. These antitumor effects require host's effector T cells but not TLR9-positive antigen-presenting cells. Instead, CpG-Stat3 siRNA has direct immunogenic effect on AML cells in vivo upregulating major histocompatibility complex class-II, costimulatory and proinflammatory mediators, such as interleukin-12, while downregulating coinhibitory PD-L1 molecule. Systemic injections of CpG-Stat3 siRNA generate potent tumor antigen-specific immune responses, increase the ratio of tumor-infiltrating CD8(+) T cells to regulatory T cells in various organs, and result in CD8(+) T-cell-dependent regression of leukemia. Our findings underscore the potential of using targeted STAT3 inhibition/TLR9 triggering to break tumor tolerance and induce immunity against AML and potentially other TLR9-positive blood cancers.
authors.affiliation: Departments of Cancer Immunotherapeutics and Tumor Immunology and.
authors.forename: Dewan Md Sakib
authors.initials: DM
authors.lastname: Hossain
authors.forename: Cedric
authors.initials: C
authors.lastname: Dos Santos
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Anna
authors.initials: A
authors.lastname: Kozlowska
authors.forename: Hongjun
authors.initials: H
authors.lastname: Liu
authors.forename: Chan
authors.initials: C
authors.lastname: Gao
authors.forename: Dayson
authors.initials: D
authors.lastname: Moreira
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jozwiak
authors.forename: Justin
authors.initials: J
authors.lastname: Kline
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D018899:CpG Islands; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D007938:Leukemia / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma