STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity

Abstract

Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). STAT3 multitasks to ensure tumors escape immune detection by impairing antigen presentation and reducing production of immunostimulatory molecules while augmenting the release of tolerogenic mediators, thereby reducing innate and adaptive antitumor immunity. Tumor-associated myeloid cells and STAT3 signaling in this compartment are now commonly recognized as an attractive cellular target for improving efficacy of standard therapies and immunotherapies. Hereby, we review the importance and functional complexity of STAT3 signaling in this immune cell compartment as well as potential strategies for cancer therapy.

Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer

“…As mentioned above, tumor-derived factors (VEGF, IL-6, IL-10) stimulate and recruit MDSCs to the TME. In turn, MDSCs via a STAT3-mediated pathway can generate more VEGF, establishing a positive feedback loop, which sustains their population and their angiogenic activity [18,63,64]. Casein kinase 2 (CK2) production, which is considered to be an angiogenic contributor, is also under the auspices of STAT3, both in MDSCs and cancer cells [65].…”

“…Some other factors contributing to MDSC-related angiogenesis and pre-metastatic enablement are bombina variegata peptide 8 (Bv8) [18,58,63], platelet-derived growth factor (PDGF) [58,59] and basic fibroblast growth factor (bFGF) [58,63]. These factors are hailed as alternative vasculature-creating mechanisms, but equally effective and perhaps overlapping, since they use similar signaling pathways (extracellular-related kinase (ERK)/Akt or mitogen-activated protein kinase (MAPK)), while the tumor-activated pSTAT3 pathway in MDSCs results in their generation [58,64]. Kuo et al detected that CXCL17 supported de novo angiogenesis and lung metastasis by means of PDGF expressing CD11b + Gr-1 + MDSC in mice [70].…”

“…Most notably, miRNA-126α, from MDSC-derived exosomes and tumor-derived exosomes (TEXs), was able to sustain MDSCs and promote angiogenesis, while conveying chemoresistance [25,38,80,81]. Specifically, miR-155 and miR-21 induced MDSCs in the TME to acquire a more immunosuppressive function, while simultaneously facilitated tumor growth via activation of the STAT3 pathway [25,64]. miR-9 contained in MDSC-derived exosomes and TEXs was shown to increase the immunosuppressive activity of MDSC and promote angiogenesis by reprogramming endothelial cells [49,81].…”

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

“…STAT3, which has been extensively studied, prevents the apoptosis of MDSCs and promotes the expansion of MDSCs by mediating the expression of apoptosis inhibitors, including Bcl-XL, cyclin D and c-Myc [20][21][22]. In addition, activation of STAT3 drives the production of the calcium-binding protein S100A8/9, which is an inflammatory protein, and increases the accumulation of MDSCs by limiting dendritic cell (DC) differentiation [23]. Arginase 1 (ARG1) is also a downstream target of STAT3 in circulating and infiltrating MDSCs [24].…”

Adoptive Cell Therapy: A Novel and Potential Immunotherapy for Glioblastoma

“…This activation of STAT3 may not be induced by its intrinsic mutations but by upstream signaling molecules such as EGFR mutations, overexpression of interleukin 6 (IL-6) and protein kinase C (PKC) (115)(116)(117). There are certain mechanisms by which STAT3 activation can induce immune tolerance: (i) by increase of M2 like macrophages and microglia (118); (ii) through the recruitment and accumulation of Treg cells (119,120); and (iii) via the suppression of DCs' maturation (121). The administration of WP1066 (a molecule inhibitor of p-STAT3) reverses immunosuppression in GBM patients and a clinical trial of phase I is on the way (NCT01904123) (122).…”