Abstract 1570: STAT3 inhibition allows for TLR9-induced reprogramming of acute myeloid leukemia into antigen-presenting cells to generate T-cell mediated immune responses
Authors: Yu-Lin Su, Dongfang Wang, Priyanka Duttagupta, Hiqing Li, Ya-Huei Kuo, Guido Marcucci, Marcin Kortylewski
Journal: Cancer Research (2021)

Abstract Signal transducer and activator of transcription factor 3 (STAT3) is commonly activated in acute myeloid leukemia (AML) and known for supporting cancer cell proliferation and survival. Recently, we demonstrated that STAT3 also plays a critical role ensuring AML immune evasion. Intravenous injections of a bi-specific oligonucleotides (CpG-STAT3 decoy inhibitors) blocked STAT3 activity and induced TLR9 signaling in Cbfb/MYH11/Mpl (CMM) AML cells, thereby resulting in immunogenic effects and T cell-mediated immune responses and leukemia regression. To understand the molecular mechanisms of AML differentiation and immunogenicity, we performed global gene expression analysis of leukemic cells treated in vivo using CpG-STAT3 decoy strategy or an inducible STAT3silencing. Transcriptional profiling revealed the upregulation of myeloid cell differentiation related genes, such as Irf8, Cebpa, and Gadd45A with reduction of oncogenic Runx1 and Run1t1 in CMM leukemic cells after CpG-STAT3dODN but not after control treatments. CpG-STAT3dODN treatment also upregulated set of antigen-presentation related genes, such as CIIta, Il12a, and Ifng in CMM AML cells. Importantly, the induction of Irf8 and Cebpa, with the concomitant suppression of Runx1 were found specifically in the subset of differentiated CD11b+ CMM cells but not in the bulk CD11b- leukemic cells. Similar transcriptional effects were triggered in CMM leukemic cells by the combination of inducible STAT3 silencing and TLR9 stimulation in vivo but not by either of these treatments alone. These effects were likely related to epigenetic reprogramming of leukemic cells as indicated by treatment-induced changes in the expression and protein levels of STAT3 regulated DNA methyltransferases, DNMT1 and DNMT3a/b. Furthermore, our studies suggest that STAT3-inhibition/TLR9-stimulation triggers immunogenic effects also in a xenotransplanted human FLT3-ITD MV4-11 leukemia in humanized mice. These effects were augmented by a combination with clinically-relevant demethylating agent (decitabine) and resulted in the differentiation of AML cells into CD11b+HLA-DR+CD86+ antigen-presenting cells (APCs) and increased ratio of CD8+ to regulatory T cells in the bone marrow, thereby reducing leukemia burden. Our results suggest that eliminating STAT3 permits the TLR9-driven reprogramming of AML cells into APCs to unleash T cell-mediated responses against leukemia. Citation Format: Yu-Lin Su, Dongfang Wang, Priyanka Duttagupta, Hiqing Li, Ya-Huei Kuo, Guido Marcucci, Marcin Kortylewski. STAT3 inhibition allows for TLR9-induced reprogramming of acute myeloid leukemia into antigen-presenting cells to generate T-cell mediated immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1570.