The Multifaceted Role of STAT3 in NK-Cell Tumor Surveillance

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses in vivo. In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.

Natural killer cell memory precedes HLH in monozygotic twins discordant for chronic active Epstein-Barr virus disease

“…STAT3 underlies many complex mechanisms of both tumorigenesis and NK cell immune function; our findings demonstrate it may also be a suitable target for prevention of NK memory priming as a third pathogenic aspect to CAEBV. 23 Our results highlight that it is crucial to initiate early treatment of CAEBV with HSCT or cytokine inhibitors, before EBV infected NK cells establish a memory population, and suggest that further investigation into the effects of memory-priming cytokines and STAT3 inhibitors may present new therapeutic opportunities.…”

Articular Cartilage Regeneration via Induced Chondrocyte Autophagy by Sustained Release of Leptin Inhibitor from Thermo‐Sensitive Hydrogel through STAT3/REDD1/mTORC1 Cascade

“…The STAT3 protein, belonging to the STAT family, serves as a versatile transcription factor implicated in numerous physiological processes, such as cellular proliferation and programmed cell death. [16][17][18] In their study, Macchi et al discovered that leptin induced an up-regulation of STAT3 phosphorylation in HepG2 cells. [19] Additionally, previous observations have indicated that leptin facilitates the progression of OA through the activation of the STAT3 signaling pathway.…”

Targeting Tumor Microenvironment Akt Signaling Represents a Potential Therapeutic Strategy for Aggressive Thyroid Cancer

“…We next examined the potential signaling pathways that might mediate the effects of tumor stromal cells on CSCs. According to the findings in recent studies, there are several signaling pathways, including JAK/STAT [ 59 , 60 , 61 , 62 , 63 ], PI3K/Akt [ 64 , 65 , 66 , 67 , 68 , 69 , 70 ], NF-kB [ 71 , 72 , 73 , 74 , 75 , 76 ], and TGF-β signaling [ 77 , 78 , 79 , 80 , 81 , 82 , 83 ], that could possibly be mediating the stromal cell functioning in PTC, as these signaling pathways have been found to be involved in the effects of stromal cells on tumor cells [ 59 , 60 , 61 , 62 , 63 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ]. To unveil the potentially engaged signaling pathways, we examined the expression of specific molecules that indicate different signaling pathway activities with Western blotting analyses.…”