Thursday, May 19, 2022
5/19/2022
Signal Transducer and Activator of Transcription 3 (STAT3) is an oncogenic transcription factor (TF) and a central immune checkpoint regulator. Tumorigenic and tolerogenic roles of STAT3 in acute myeloid leukemia (AML) and other human cancers, as well as in the tumor-associated immune cells are well-defined and provide solid scientific premises for therapeutic STAT3 inhibition. To overcome the challenge imposed by lack of pharmacological inhibitors of STAT3, we recently developed a strategy for myeloid cell-selective STAT3 inhibition in vivo. Tethering to a synthetic Toll-like Receptor 9 (TLR9) agonists, CpG ODNs, allowed for targeted delivery of a STAT3 decoy oligodeoxynucleotide (STAT3dODN) into myeloid cells, such as AML cells and tumor-associated immune cells. Our preliminary studies demonstrated that intravenous injections of CpG-STAT3dODN lead to regression of disseminated human and mouse acute myeloid leukemia (AML) in murine models. In immunocompetent mice, STAT3-blocking/TLR9-stimulation triggered differentiation of leukemic cells to antigen-presenting cell (APC) phenotype rather than direct cytotoxicity. The immunogenicity of AML-APCs induced systemic CD8/CD4 T cell-mediated immunity and eliminated disseminated leukemia, including leukemic stem/progenitor cells, with no detectable toxicities to normal immune/hematopoietic stem cells. We propose to elucidate molecular/cellular mechanisms of CpG- STAT3dODN-induced AML immunogenicity and to characterize role of T cell-mediated immunity in AML rejection. Better understanding of the CpG-STAT3dODN effect on leukemia cell and T cell compartments will allow for the design of optimal combination of TLR9-targeted STAT3 inhibition with T cell-based therapies which will be validated within this proposal. These studies will accelerate development of novel, effective and safe nucleotide-based immunotherapeutic strategies for cell-selective targeting of STAT3 in AML and potentially other hematologic malignancies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
