Leukemia cell–targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity

• Published in: Blood Vol. 123; no. 1; pp. 15 - 25
• Main Authors: Hossain, Dewan Md Sakib, Dos Santos, Cedric, Zhang, Qifang, Kozlowska, Anna, Liu, Hongjun, Gao, Chan, Moreira, Dayson, Swiderski, Piotr, Jozwiak, Agnieszka, Kline, Justin, Forman, Stephen, Bhatia, Ravi, Kuo, Ya-Huei, Kortylewski, Marcin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-01-2014; American Society of Hematology
• Subjects: Animals; CD8-Positive T-Lymphocytes - cytology; Cell Line, Tumor; CpG Islands; Gene Expression Regulation, Leukemic; Gene Silencing; Immune Tolerance; Interferon-gamma - metabolism; Leukemia - immunology; Leukemia - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Plenary Paper; RNA, Small Interfering - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Toll-Like Receptor 9 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-07-517987

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.
•Blocking STAT3 in acute myeloid leukemia cells stimulates their TLR9-induced immunogenicity and antigen-specific activation of CD8+ T cells.•Systemic delivery of CpG-Stat3 siRNA generates potent adaptive immune responses eradicating disseminated acute myeloid leukemia in vivo.