STAT3: the “Achilles” heel for AML?

Abstract

In this issue of Blood, in a series of elegant studies in a transplantable mouse model of acute myeloid leukemia (AML), Hossain et al¹ show that systemic signal transducer and activator of transcription 3 (STAT3) blocking/TLR9 triggering can eradicate established AML through an immune-mediated mechanism.

STAT3 activation pathways in AML (A) and the potential role of STAT3 inhibitors (B).

Cancer growth is determined by cell-intrinsic phenomena, such as activation of transcription programs responsible for cancer cell proliferation, and cell-extrinsic phenomena, such as an immune-mediated cancer surveillance. The identification of a number of leukemia-specific antigens and recent clinical advances in cancer immunotherapy underscore the potential for safer and more effective AML treatments.² However, many immunotherapies such as cancer vaccines have often shown insufficient antitumor effects,³ likely due to “immune editing” by the strongly immunosuppressive AML microenvironment.

One of the key transcription factors involved in tumorigenesis is STAT3, which is aberrantly activated (through tyrosine phosphorylation) in the majority of cancers.⁴ Constitutive STAT3 activity induces specific target genes that 1stimulate cell proliferation, prevent apoptosis, promote angiogenesis, and facilitate tumor immune evasion. STAT3 has also been shown to play a significant role in subversion of host immune responses and is responsible for the accumulation and the activation of immunosuppressive cells, such as regulatory T cells (Treg), Th17 cells, and myeloid-derived suppressor cells, and the absence of functional dendritic cells (DCs).^4,5 Thus, targeting STAT3 both in cancer cells and immunosuppressive immune cells may result in restoration of immunocompetence, making it an attractive molecular target for the development of novel cancer therapeutics.

A number of therapeutic strategies have explored selective inhibition of STAT3 signaling, including small molecule inhibitors and compounds, protein inhibitors, dominant-negative STAT3 mutants, antisense RNA, and interference oligonucleotides.⁶ In a seminal paper in 2005, the authors showed that systemic administration of STAT3 inhibitors not only inhibited tumor growth but also reduced the production of immunosuppressive cytokines while increasing production of inflammatory cytokines and chemokines, leading to augmentation of DC function and cytotoxic T-cell induction.⁷ They later showed that in the same way, ablating STAT3 in hematopoietic cells results in rapid activation of innate immunity by CpG (a TLR9 ligand), with enhanced production of interferon-γ, tumor necrosis factor α, and interleukin-12 and activation of macrophages, neutrophils, and natural killer (NK) cells associated with eradication of B16 melanoma tumors.⁸

STAT3 has also been shown to play a significant role in promoting AML cell proliferation and survival,⁹ but whether it also plays a role in AML-induced immune evasion remains to be determined. In the present study, the authors extend from their previous work to investigate whether silencing STAT3 using small interfering RNA (siRNA) increases CpG-induced DC maturation, T-cell activation, and AML-induced immunity in a genetic mouse model of Cbfb/MYH11/Mpl⁺-induced leukemia, which closely resembles human AML with inv(16)(p13:q22) gene fusion. The authors report that CpG-Stat3 siRNA-induced leukemia regression is primarily dependent on correction of the immunosuppressive microenvironment of AML rather than on direct tumor cell killing. In a series of elegant experiments, they showed that CpG-Stat3 siRNA facilitates differentiation of AML blasts to antigen-presenting cells (APCs) with DC phenotype, with upregulation of major histocompatibility class II and costimulatory molecules. Moreover, systemic STAT3 blocking/TLR9 triggering was shown to reverse immune tolerance by downregulating expression of the coinhibitory PD-L1 molecule and reducing numbers of Tregs while increasing recruitment of activated CD8 T cells into major leukemia reservoirs, such as spleen and bone marrow.

These findings show that STAT3 is a key molecule favoring persistence of AML through 3 mechanisms: promoting proliferation and survival, preventing AML differentiation to functional DCs, and blocking T-cell function through other pathways (see figure). However, while the murine AML model may be an accurate representation of human core binding factor leukemias, the mouse immune milieu may be a less accurate representation of its human counterpart. Nevertheless, these findings encourage us to explore the role that STAT3 plays in our ability to achieve and maintain remissions in AML and raise the exciting prospect of therapeutically targeting STAT3 in conjunction with remission induction treatment. A diversity of abnormalities in NK cells, T cells, and APC function have been described in AML. Could they all be derived from STAT3 overexpression in the leukemia cell? More studies with human AML are now indicated to explore the downstream events following leukemia-cell STAT3 signaling. An important question is whether the least-differentiated leukemia-initiating cells, as well as the more mature AML blasts, can suppress immunity. Such findings might predict whether the immune suppression persists into remission. Critically, we need to explore the relationship between STAT3 activity and outcome in patients with AML. Could STAT3 expression serve as a predictive factor for the maintenance of remission? Do leukemia subtypes with more favorable outcomes have less STAT3 expression? Supporting data from human AML would form the basis for trials of STAT3 inhibition to improve treatment outcomes.