In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-334-LB-334
Abstract:
STAT3 transcription factor plays central role for survival, metastasis and immune evasion of many solid and blood tumors. In acute myeloid leukemia (AML), STAT3 is a critical node in signaling from numerous tyrosine kinases. Thus, it is an attractive but also elusive pharmacological target. We have recently shown that linking siRNA molecules to Toll-like receptor 9 (TLR9) ligands, CpG oligonucleotides, allows for cell-specific siRNA delivery in vivo. CpG-STAT3 siRNA conjugates induce RNAi in both mouse and human immune cells resulting in potent immunostimulatory effects. TLR9 is also commonly expressed in blood cancers, such as AML. We assessed whether targeting STAT3 in both leukemic and in tumor-associated immune cells using CpG-STAT3 siRNA can augment antitumor effects. We used orthotopic models of mouse Cbfb-MYH11 leukemia on 129Sv and C57BL/6 genetic backgrounds, which closely mimic human inv(16) AML. Our results demonstrated that intravenous injections of CpG-STAT3 siRNA (5 mg/kg), but not control oligonucleotides, into mice with established leukemia (1-2 weeks after challenge) resulted in elimination of leukemic cells from bone marrow, spleen, lymph nodes and blood. Furthermore, prior in vivo CpG-STAT3 siRNA treatment inhibited the engraftment and leukemia onset in secondary recipient mice. We found that these therapeutic effects depended on intact immune system, as CpG-STAT3 siRNA failed to eliminate leukemia in immunodeficient mice. In fact, systemic STAT3 targeting led to immune activation not only of DCs but also of AML cells as measured by cell surface expression of immune markers (MHC II, CD40, CD80 and CD86), secretion of IL-12 and IFNγ as well as induction of T cell proliferation. CpG-STAT3 siRNA treatment also reduced accumulation of tolerogenic regulatory T cells and myeloid-derived suppressor cells. The antibody-mediated depletion experiments confirmed the critical role of CD8 T cells in CpG-STAT3 siRNA-induced antitumor immunity. Finally, our preliminary studies confirmed that this strategy allows for targeting STAT3 also in primary human CD34+ AML cells. These findings indicate the potential of using CpG-STAT3 siRNA alone or in combination with T cell-based immunotherapeutic strategies for treatment of AML and potentially other TLR9-positive blood cancers. This project described was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA155367 awarded to M.K. Citation Format: Sakib D M Hossain, Cedric Dos Santos, Qifang Zhang, Hongjun Liu, Piotr Swiderski, Claudia Kowolik, Stephen Forman, Ravi Bhatia, Ya-Huei Kuo, Marcin Kortylewski. CpG-STAT3 siRNA for two-pronged immunotherapy of acute myeloid leukemia . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-334. doi:10.1158/1538-7445.AM2013-LB-334
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-LB-334
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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