A novel tumor-promoting mechanism of IL6 and the therapeutic efficacy of tocilizumab: Hypoxia-induced IL6 is a potent autophagy initiator in glioblastoma via the p-STAT3-MIR155-3p-CREBRF pathway

Abstract

Hypoxia induces protective autophagy in glioblastoma cells and new therapeutic avenues that target this process may improve the outcome for glioblastoma patients. Recent studies have suggested that the autophagic process is upregulated in glioblastomas in response to extensive hypoxia. Hypoxia also induces the upregulation of a specific set of proteins and microRNAs (miRNAs) in a variety of cell types. IL6 (interleukin 6), an inflammatory autocrine and paracrine cytokine that is overexpressed in glioblastoma, has been reported to be a biomarker for poor prognosis because of its tumor-promoting effects. Here, we describe a novel tumor-promoting mechanism of IL6, whereby hypoxia-induced IL6 acts as a potent initiator of autophagy in glioblastoma via the phosphorylated (p)-STAT3-MIR155-3p pathway. IL6 and p-STAT3 levels correlated with the abundance of autophagic cells and HIF1A levels in human glioma tissues and with the grade of human glioma, whereas inhibition of exogenous or endogenous IL6 repressed autophagy in glioblastoma cells in vitro. Knockdown of endogenous MIR155-3p inhibited IL6-induced autophagy, and enforced expression of MIR155-3p restored the anti-autophagic activity of IL6 inhibitors. We show that the hypoxia-IL6-p-STAT3-MIR155-3p-CREBRF-CREB3-ATG5 pathway plays a central role in malignant glioma progression, with blockade of the IL6 receptor by tocilizumab demonstrating a certain level of therapeutic efficacy in a xenograft model in vivo, especially in combination with temozolomide. Moreover, tocilizumab inhibits autophagy by promoting tumor apoptosis. Collectively, our findings provide new insight into the molecular mechanisms underlying hypoxia-induced glioma cell autophagy and point toward a possible efficacious adjuvant therapy for glioblastoma patients.

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

“…The induction of myeloid B7-H4 was similarly shown to be IL6/STAT3 dependent (32), supporting the notion that IL6 can activate redundant immunosuppressive mechanisms (79). Apart from mediating immunosuppression, GBM-derived IL6/STAT3 signaling has also been implicated in tumor proliferation (52,80), invasion (81,82), angiogenesis (82), autophagy (83), and glioma stem cell maintenance (66). In GBM explant, GL261, and CT-2A cells, we observed decreased proliferation with IL6 blockade.…”

Cellular Stress Response to Varicella-Zoster Virus Infection of Human Skin Includes Highly Elevated Interleukin-6 Expression

“…A recent relevant paper describes a previously unrecognized link between IL-6 and enhanced autophagy via the STAT3-MIR155-3p-CREBRF-CREB3-ATG5 pathway [33]. In another study, VZV infection led to increased phosphorylation of STAT3, evidence for the first step in the IL-6-STAT3 autophagy pathway [34].…”

The Emerging Role of Myeloid-Derived Suppressor Cells in the Glioma Immune Suppressive Microenvironment

“…Recently, Qin et al proved that S100A9 peptide-Fc fusion (peptibody) reagents can deplete blood and splenic MDSCs in mouse tumor models (107,108). Further, many researches proved that anti IL-6 therapy showed potential benefits for treating various human cancers including glioma (109,110), Sumida et al found that an anti-IL-6 receptor monoclonal antibody (mAb) could eliminate MDSCs and inhibit tumor growth by enhancing T-cell responses, and that its therapeutic effect was enhanced by combination with gemcitabine (111). Together, these data suggest that MDSCs can be directly depleted using various agents, including chemotherapy drugs, peptides, and mAbs; however, the mechanisms underlying MDSC elimination require further elucidation.…”