Interleukin‐6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

Abstract

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

Regulatory network analysis of LINC00472, a long noncoding RNA downregulated by DNA hypermethylation in colorectal cancer

“…In total, the network had 2684 links with 343 ceRNA interactions, 20 miRNA‐ LINC00472 regulations, 1 TF‐ LINC00472 regulatory relationship, 3 RBPs interacting with LINC00472 and 2318 PPIs among these proteins (Figure , Table S3). In the regulatory network, the TF was signal transducer and activator of transcription‐3, which had been reported to be involved in many types of cancer . Three RNA‐binding proteins are heterogeneous nuclear ribonucleoprotein A1 ( HNRNPA1 ), heterogeneous nuclear ribonucleoprotein H1 ( HNRNPH1 ) and fused‐in‐sarcoma.…”

“…In the regulatory network, the TF was signal transducer and activator of transcription-3, which had been reported to be involved in many types of cancer. 35 Three RNA-binding proteins are heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) and fused-in-sarcoma. HNRNPA1 expression level was higher in low-stage CRC compared with that of high-stage CRC, 36 while HNRNPH1 was downregulated in CRC.…”

IL‐6 promotes metastasis of non‐small‐cell lung cancer by up‐regulating TIM‐4 via NF‐κB

“…10 As expected, our study found that IL-6 promoted TIM-4 expression in NSCLC cell lines via NF-κB pathway. In addition to NF-κB, STAT3 is another key factor in IL-6 signalling pathway, 34,35 and it has been documented that IL-6 promoted lung cancer development and progression by activating STAT3. 36,37 Another study found that IL-6 could induce immunosuppressive factor PD-L1 expression on peripheral myeloid cells through STAT3-dependent mechanism.…”

Circadian Regulation of Immunity Through Epigenetic Mechanisms

“…For example, in dendritic cells (DC) histone deacetylation is crucial for differentiation (Nencioni et al, 2007). Also, the TF signal transducer and activator of transcription 3 (STAT3) controls dendritic function by regulating target genes involved in DC differentiation, such as the IDO enzyme and the HLA class II genes (Sun et al, 2009;Cacalano, 2016;Kitamura et al, 2017). Importantly, the circadian HDAC SIRT1 is a master regulator of STAT3 function by deacetylation, hereby inactivating it (Nie et al, 2009) (Figure 2).…”