STAT3 signaling in immunity

Abstract

The transcriptional regulator STAT3 has key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3 associate with diseases such as immunodeficiency autoimmunity and cancer. Strikingly, however, either hyperactivation or inactivation of STAT3 results in human disease, indicating tightly regulated STAT3 function is central to health. Here, we attempt to summarize information on the numerous and distinct biological actions of STAT3, and highlight recent discoveries, with a specific focus on STAT3 function in the immune and hematopoietic systems. Our goal is to spur investigation on mechanisms by which aberrant STAT3 function drives human disease and novel approaches that might be used to modulate disease outcome.

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

“…[6, 8, 11, 12] Multitasking in the tumor microenvironment reflects essential function of STAT3 in wound healing and resolution of inflammation, at least partly though shifting transcriptional activity of NF-κB from pro-inflammatory to tumorigenic target genes. [13, 14] Therefore, STAT3 can be considered the central immune checkpoint regulator and the nodal point for immunosuppressive signaling in tumor-associated myeloid cells. [8] This unique role and the contribution of STAT3 to survival of cancer cells, provide a strong rationale for therapeutic interventions targeting this molecule.…”

“…[8] This unique role and the contribution of STAT3 to survival of cancer cells, provide a strong rationale for therapeutic interventions targeting this molecule. [8, 13] Importantly, genetic loss of STAT3 activity in humans is not lethal although it leads to complex immunodeficiency (autosomal-dominant hyper-immunoglobulin E syndrome; AD-HIES) associated with skin and lung infections, eosinophilia and high levels of IgE. [15] These manifestations are likely caused by impaired development of Th17 cells, and follicular helper T cells that in turn results in abnormal B cell functions.…”

“…[21] Beyond such toxicities, broad inhibition of Jak/STAT signaling may impede IFN-mediated antitumor immunity and/or STAT3-mediated generation of memory T cells. [13] These observations emphasize the need for both molecular and cellular selectivity in targeting STAT3 in order to maximize immunotherapeutic efficacy while reducing potential toxicities. Oligonucleotide-based therapeutics (ONTs), such as siRNA, antisense oligonucleotides (ASO) or decoy oligodeoxynucleotides (dODN), emerged as potential alternatives to small molecule STAT3 inhibitors.…”

“…[40, 46] At the same time, the temporary inhibition of STAT3, usually limited to 2–4 weeks, did not affect generation of DCs which is a known effect of Stat3 ablation. [13, 40] In fact, local intratumoral injections of CpG-STAT3siRNA drastically improved effector functions of adoptively transferred CD8 + T cells, increasing their killing activity and tumor infiltration. Improved tumor antigen-presentation also contributed to the synergistic effect of CpG-STAT3siRNA combined with localized tumor RT.…”

STAT3 Expression in Host Myeloid Cells Controls Graft-versus-Host Disease Severity

“…Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family and plays a central role in regulating innate and adaptive immune responses 17, 18 . STAT3 signaling in T cells exacerbates both acute and chronic GVHD potentially due to its essential role for donor T cell activation and inflammatory T H 17 cell differentiation 19–26 .…”