Sage Journals: Discover world-class research

Abstract

Immunotolerance is one of the hallmarks of malignant tumors. Tumor cells escape from host immune surveillance through various mechanisms resulting in tumor progression and therapeutic resistance. Interlukin-6 is a proinflammatory cytokine involved in many physiological and pathological processes by integrating with multiple intracellular signaling pathways. Aberrant expression of interlukin-6 is associated with the growth, metastasis, and chemotherapeutic resistance in a wide range of cancers. Interlukin-6 exerts immunosuppressive capacity mostly by stimulating the infiltrations of myeloid-derived suppressor cells, tumor-associated neutrophils, and cancer stem-like cells via Janus-activated kinase/signal transducer and activator of transcription 3 pathway in tumor microenvironment. On this foundation, blockage of interlukin-6 signal may provide potential approaches to novel therapies. In this review, we introduced interlukin-6 pathways and summarized molecular mechanisms related to interlukin-6-induced immunosuppression of tumor cell. We also concluded recent clinical studies targeting interlukin-6 as an immune-based therapeutic intervention in patients with cancer.

Keywords

Interlukin-6 immunosuppression cancer myeloid-derived suppressor cells targeted therapy

Introduction

Chronic inflammation contributes to the initiation and progression of various cancers.^1,2 Immunosuppression may be a key mechanism involved in the inflammation-induced tumorigenesis by restraining immune surveillance.^3,4 Adaptive immunity effectively protects the body from cancer progression and induces tumor dormancy.^5–7 Nevertheless, by recruiting monocytes/macrophages, myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs), activated innate and humoral immune responses cancel the adaptive immunity protection, followed by the generation of tumor growth–dependent stroma and inhibition of immunocompetence in cancer patients.^8–11

Interlukin-6 (IL-6), known as a pleiotropic cytokine, is produced by multiple immune cells. Previous studies showed that aberrant expression of IL-6 detected in various cancers (e.g. breast cancer, lung cancer, liver cancer, colorectal cancer, prostate cancer, melanoma) in both messenger RNA (mRNA) and protein level was relevant to oncogenesis, tumor progression, multidrug resistance, and poor clinical outcomes in vitro and in vivo.^12–15 In clinical specimens, elevated IL-6 also has been associated with advanced stage and poor prognosis of patients with cancer. Mechanically, IL-6 regulates the growth and progression of malignancies by inhibiting apoptosis, stimulating angiogenesis, and inducing drug resistance via several signaling pathways, especially the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK/STAT3) transduction pathway. IL-6 acts as a major factor to regulate innate immune response by stimulating the production of MDSCs, neutrophils, macrophages, and C-reactive protein,^16–18 as well as by controlling antitumor T-lymphocyte responses.^12,19–21 Accordingly, blocking IL-6 signaling may provide a novel therapeutic target and resensitize cancer cells to immunotherapies. For instance, a phase II trial evaluating the clinical benefit of breast and pancreatic cancer patients in the siltuximab (an anti-IL-6 agent) treatment has been completed (NCT00841191).

In this review, we concluded the intracellular IL-6 signaling pathways and described current understandings of IL-6 in tumor immunosuppression. Recent advances in targeted IL-6 therapies in cancers were also summarized.

Structure and intracellular signaling pathways of IL-6

IL-6, which can be secreted by monocytes, T-cells, fibroblasts, and endothelial cells, is a 20-kDa glycoprotein consisting of 184 amino acids which form a typical four-helix structure linked by loops and an additional mini-helix.^22,23 The gene encoding IL-6 is located on p14–p21 of chromosome 7.²⁴ Nuclear factor (NF)-κB upregulates the transcription of IL-6 by binding to its promoter region.²⁵ Accordingly, the expression of IL-6 can be stimulated by lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), IL-1α, and all those factors which can activate NF-κB.^26,27 In physiological processes, IL-6 mainly induces hematopoiesis, antibody production, and acute-phase reactions via stimulating the production of acute-phase proteins and activating B lymphocytes and T lymphocytes.^22,28 Additionally, IL-6 is also involved in regenerative processes, such as neoangiogenesis, in the regulation of metabolism, bone homeostasis, and neural function.^29,30

IL-6 receptors embedding on cellular membrane (IL-6R) and soluble IL-6R (sIL-6R) are two existences of receptors for IL-6. IL-6R (also named CD126) and glycoprotein (gp)130 (also named CD130) constitute a cell-surface type I cytokine receptor complex which subsequently activates downstream intracellular signals relevant to proliferation and apoptosis.²⁴ sIL-6R is derived from transmembrane IL-6R by proteolysis which is mediated via a disintegrin and metalloproteinases 10 (ADAM10) and ADAM17 as well as via mRNA alternative splicing.³¹ sIL-6R is mostly detected in peripheral circulation and interacts with IL-6 to activate cells which only express gp130 but not IL-6R.^32,33 IL-6/IL-6R is acknowledged as a classic signaling mediating the anti-inflammatory reaction, whereas IL-6/sIL-6R is defined as a trans-signaling endowing IL-6 with proinflammatory characteristics.^34,35 On the grounds that the soluble form of gp130 (sgp130) has been demonstrated to be a native inhibitor of trans-signaling, artificially synthesized sgp130-dimers linked by the Fc-part of a human IgG antibody was introduced to clinical trials presently (FE999301).^36–38

JAK tyrosine kinase family is found to act as a constitutive kinase domain of gp130 which can be phosphorylated responding to IL-6.³⁹ Subsequently, activated JAK induces phosphorylated and dimerized STAT3 to translocate to nucleus and bind with DNA elements, resulting in a change in the transcription of numerous genes.^40,41 Phosphorylated STAT3 (pSTAT3) is defined as a crucial regulator basically promoting the transcription of apoptosis-related genes, for instance, BcL-XL, MCL-1, c-myc, Fas, and p53.⁴² Accordingly, IL-6/JAK/STAT3 pathway is involved in survival, proliferation, and differentiation of normal or tumor cells.^24,43 Suppressor of cytokine signaling (SOCS) feedback inhibitors, protein inhibitor of activated Stat (PIAS) proteins, and Src homology region 2 domain-containing phosphatase-1/2 (SHP-1/2) are major mediators restraining the IL-6/JAK/STAT3 pathway under physiological conditions.⁴⁴ Moreover, Ras-/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways are also two remarkable downstream pathways of IL-6 in inflammation and tumorigenesis processes. Activated Ras protein leads to the phosphorylation of MAPK signaling cascade composed of multiple serine/threonine kinases. And then, MAPK transcriptionally regulates genes associated with cell growth stimulation and the synthesis of acute-phase protein and immunoglobulin.^45,46 IL-6-activated JAK also can phosphorylate PI3K enzyme which promotes the generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) and in turn activates protein kinase B (PkB)/AKT pathway to modify cellular survival signal.^47,48 It was reported that PI3K/AKT pathway also relied on IL-6-induced RAS activation in myeloma cells.⁴⁹ In general, above three pathways are involved in tumorigenic and anti-apoptotic activities of IL-6, and a schematic signaling diagram is shown in Figure 1. Interrupting any part in this network supplies prospective strategies for cancer treatments.

Figure 1.

The diagram summarizing the major signaling pathways of IL-6 in cancers. IL-6 interacts with a cell-surface type I cytokine receptor complex, IL-6R/gp130, which subsequently activated intracellular pathways. Responding to IL-6, JAK is phosphorylated and activates STAT3. Phosphorylated STAT3-dimer then transfers to nucleus and binds DNA elements to alter the expression of genes relevant to proliferation, survival, invasion, differentiation, and apoptosis of tumor cells. Another two significant downstream pathways of IL-6 are PI3K/AKT and Ras/MAPK. PI3K/AKT activates NF-κB acting as a transcriptional regulatory factor to promote associated gene expressions. Ras/MAPK regulates genes related to cell growth stimulation and acute-phase protein and immunoglobulin synthesis. Meanwhile, RAS was reported to activate PI3K/AKT pathway in myeloma cells. sIL-6R is a soluble form of IL-6 receptor, and sgp130Fc is a monoclonal antibody invented to block this pathway. Other drugs with ability to block IL-6 pathway include anti-IL-6 agents, anti-IL-6R agents, and STAT3 phosphorylation inhibitor.

The double effects of IL-6 on immunoregulation

IL-6 regulates a vital connection between adaptive and innate immunity mainly by mediating the T cell- and B cell-mediated immune responses. It was found that IL-6 indirectly induced the differentiation of activated B cells into antibody-producing plasma cells, which then synthesize immunoglobulin subclasses, through acting on CD4⁺ T-cells to upregulate IL-21 production in vitro and in vivo.⁵⁰ Consequently, aberrant expression of IL-6 can lead to hypergammaglobulinemia and autoantibody production which contribute to the development of autoimmune and chronic inflammatory diseases.⁵¹ IL-6-defective mice model showed a decrease in B-cell-related immune responses, particularly in the response associated with a T-cell-dependent antigen.⁵² IL-6 cooperates with transforming growth factor-β (TGF-β) to stimulate the differentiation of naive T-cell into T helper 17 (Th17) cell which triggers the inflammation reaction and leads to various autoimmune diseases.^53–55 There is a positive feedback that IL-6 stimulates Th17 to secrete IL17 which activates NF-κB and in turn to increase the gene expression of IL-6.⁵⁶ Whereas IL-6 downregulates the fraction of regulatory T (Treg) cell which restrains the proliferation and related antibody secretion of effector T cell.^57,58 Upregulation of the Th17/Treg proportion is involved in destructing immunological tolerance followed by the development of autoimmunity. Thus, IL-6 maintains the dynamic balance between Th17 and Treg.⁵¹ In this aspect, IL-6 can be regarded as a proinflammatory cytokine which is essential for immune homeostasis.⁵⁸

In another aspect, IL-6/STAT3 cascade inhibits the expressions of major histocompatibility complex (MHC) class II and CD86 molecules on the surfaces of dendritic cells (DCs) in vivo, resulting in the retardation of cancer-related antigen presentation.^59,60 The dysfunction of DCs also attenuates CD4⁺ T-cell-mediated antitumor immunity responses, and inhibition of IL-6 slows down tumor growth by restoring T-cell activity in tumor-bearing mice model.^61,62 Moreover, IL-6 is involved in the differentiation and expansion of MDSCs, which can inhibit T-cell via multiple molecular mechanisms.⁶³ Overall, IL-6 may play a double role in immunoregulation under pathological conditions.

Interaction between IL-6 and immune resistance in tumor microenvironment

IL-6 and MDSCs

MDSCs, which were described as a heterogeneous population of immature myeloid cells at different stages of differentiation,⁶⁴ negatively affected immune responses during inflammation, infection, and cancer via inhibiting T-cell activity and upregulating immunosuppressive cells and cytokines.^65–67 Circulating MDSCs were found to be chemoattracted to the tumor site by tumor-derived factors, such as IL-6, chemokine (C-X-C motif) ligand 8 (CXCL8), interferon-γ (IFN-γ), TGF-β, and IL-4. Part of MDSCs could differentiate into tumor-associated macrophages (TAMs) in tumor environment.^64,68,69 In addition to the role of immunosuppression, MDSCs have also been identified as a promoter in tumor angiogenesis, invasion, and metastasis. Diaz-Montero et al.⁷⁰ investigated that circulating levels of MDSCs were significantly higher in 106 cancer patients with newly diagnosed solid tumors of all stages than in normal volunteers; moreover, among stage IV patients, both percentages and absolute numbers of MDSCs were associated with metastatic tumor burden. Decreased expansion of MDSCs could retard tumor progression by enhancing inflammation process.⁷¹

IL-6 was referred to be a pivotal downstream factor of IL-1β-induced stimulation of MDSCs. Tumor-derived IL-6 compensated the accumulation of MDSCs and was relevant to the primary and metastatic tumor growth in IL-1β-deficient mice.⁷¹ MDSCs also could directly respond to IL-6 via IL-6R which was steadily expressed on their surfaces.⁷¹ Studies revealed that IL-6 produced by tumors was involved in defective myeloid cell maturation and impairment of myelopoiesis which resulted in accumulation and expansion of MDSCs in tumor-bearing hosts mainly via activating JAK2/STAT3 signaling pathway.^72,73 In line with this notion, Xu et al.⁷⁴ recently showed that drug-resistant hepatocellular cancer cells–derived IL-6 was the major candidate in mediating the expansion and activity of MDSCs using an anti-IL-6 neutralizing antibody that caused a decreased population and immunosuppressive role of MDSCs in vitro culture model and in vivo mouse model. In the 4-NQO-stimulated esophageal squamous cell carcinoma (ESCC) mouse model, IL-6 not only recruited CD11b⁺CD14⁺HLA-DR⁻ myeloid cells, a novel subset of MDSCs, but also enhanced the functional activities of MDSCs. Increased production of reactive oxygen species (ROS) and arginase 1 (ARG1), which were involved in MDSCs-induced T-cell inhibition, were detected in IL-6-treated CD14⁺ cells.⁷⁵ In the treated mice, the level of MDSCs was positively associated with the increased possibility of esophageal invasive carcinoma formation, suggesting that IL-6-induced MDSCs might facilitate growth and progression of ESCC in vivo.⁷⁵ Moreover, higher levels of IL-6 and CD11b⁺CD14⁺HLA-DR⁻ myeloid cells were detected by flow cytometry in the peripheral blood of patients diagnosed with ESCC compared with healthy individuals.⁷⁵ In breast cancer, IL-6 activated the STAT3/NF-κB/IDO pathway in MDSCs which was conducive to generate an immunosuppressive tumor microenvironment and lymph node metastasis.^76,77 Taking above mechanisms and interactions into consideration, targeting MDSCs and IL-6 might be promising strategies for intervening immunization-mediated tumorigenesis and tumor progression.

IL-6 and TANs

Neutrophils were always recognized as a proinflammatory factor mediating injury restoration and preventing tumor progression via cytotoxic effects as well as vascular endothelium damage.⁷⁸ In recent studies, TANs were proposed to promote tumorigenesis and angiogenesis and be associated with poor clinical outcome and heavy tumor burden.^79–82 IL-6 and granulocyte-colony stimulating factor (G-CSF) endowed neutrophils with cancer-promoting functions before they infiltrated into the tumor nests not only by modulating related gene expressions but also by reducing neutrophil degranulation.⁸³ The augmented STAT3 activation and inefficient PI3K and p38 MAPK pathways resulted in reduction of Rab27a in neutrophils, which downregulated the spontaneous release of azurophilic granules from neutrophils.⁸³ Consequently, costimulation with G-CSF and IL-6 enhanced STAT3 activation and inhibited activation of PI3K and p38 MAPK pathways to increase the expressions of Mmp9 and Bv8 genes and suppress the release of MPO, NE, TRAIL, and defensins from neutrophils, thus attenuated neutrophil degranulation, conducing neutrophils to promote tumor angiogenesis and tumor growth.⁸³ It was reported that IL-6 secreted by gastric cancer–derived mesenchymal stem cell (GC-MSC) maintained the long-term functional activation of neutrophils through STAT3–extracellular signal–regulated protein kinases 1 and 2 (ERK1/2) pathway, which in turn stimulating the metastatic and angiogenic potentials of gastric cancer and promoting the conversion from normal MSC to cancer-associated fibroblast (CAF) in tumor stroma.⁸⁴ Overall, it is reasonable to conclude that IL-6-induced resistance to immune killing occurs mainly by attracting the TANs to tumor milieu and by attenuating and reversing the proinflammatory effects of neutrophils in tumor microenvironment.

IL-6 and epithelial–mesenchymal transition

Epithelial–mesenchymal transition (EMT) is an essential program in multiple developmental processes. In addition to promoting the transition from epithelium to mesenchymal during wound healing and tumor metastasis, EMT was also demonstrated to induce the migration of embryonic epithelial cell during early embryogenesis.^85,86 EMT-activated metastatic cascades which contributed to the loss of cell–cell junctions and cell polarity could endow tumor cell with invasive characteristics.⁸⁷ EMT is not only sufficient to support primary tumor growth, but may also facilitate the formation and establishment of secondary tumor.

The positive correlation between IL-6 and EMT

The involvements of IL-6 in starting the EMT program and promoting metastatic potential were first shown in estrogen receptor-alpha (ER-α)-positive human breast cancer in 2009. Stable-expressing IL-6 breast cancer cell line (MCF-7^IL-6) led to an EMT phenotype characterized by repressed E-cadherin expression and induction of Vimentin, N-cadherin, Snail, and Twist in both RNA and protein levels.⁸⁸ Functional assay in vitro certified that IL-6 enhanced the invasiveness and promoted the process of EMT.⁸⁸ Similarly, IL-6 overexpressed tumor xenograft also showed EMT changes combined with increased proliferation, advanced tumor stage, and poor histological differentiation in breast cancer.^88,89 Remarkably, there was a positive feedback loop in IL-6/STAT3/Twist pathway. IL-6 signaling pSTAT3 to subsequently transactivate Twist which inhibited the transcription of E-cadherin and contributed to EMT. Meanwhile, aberrant accumulation of Twist led to ectopic IL-6 expression and STAT3 activation, suggesting an autocrine manner involved in IL-6-mediated EMT in breast cancer cell.^88–90

EMT was generally found to facilitate metastasis in head and neck cancer patients.⁹¹ Yadav et al.⁹² first proved the significant role of IL-6 in inducing EMT changes and enhancing metastatic potential via JAK/STAT3/Snail intracellular signal in head and neck squamous cell carcinoma (HNSCC). CAL27 cell stably overexpressing IL-6 exhibited obviously reduction of E-cadherin (53%) and induction of vimentin (54%) and snail (51%).⁹² In addition, ectopic IL-6 was relevant to scattering effect which occurred when cell–cell junctions disappeared and was one of the traits of EMT progress.⁹² They also discovered that STAT3/Snail pathway stimulated IL-6-mediated EMT in CAL27 cell.⁹² Moreover, a severe combined immunodeficient (SCID) mouse xenograft model was utilized to show that higher level of IL-6 enhanced pSTAT3 and Snail proteins to promote EMT and contribute to more distant lymph nodes metastases in HNSCC.⁹² Furthermore, IL-6 treatment in cervical squamous cell carcinoma (CSCC) was proved to promote tumor growth, alter cell morphology to mesenchymal, and induce EMT by activating STAT3, especially in poorly differentiated human CSCC tissue.⁹³

Knockdown of the key transductor implicated in IL-6-induced metastatic cascade can provide an optional regimen for tumor therapies. For example, SHP2, known as an intracellular protein tyrosine phosphatase, is indispensable for the IL-6-induced EMT of breast cancer cells. It was proved that knockdown of SHP2 weakened the IL-6-induced reduction of E-cadherin and IL-6-promoted cell migration and invasion.⁹⁴ Metformin, a widely used antidiabetic agent, was found to reverse EMT and attenuate IL-6 signaling in tyrosine kinase inhibitor (TKI)-resistant cells in non-small-cell lung cancer (NSCLC). In xenograft mouse model, utilizing metformin-based combination therapy could block tumor growth which is accompanied by decreased IL-6 signaling activation and EMT.⁹⁵ Moreover, by inactivating STAT3 signal, wogonin retarded IL-6-induced EMT both in A549 cell lines and in mice model.⁹⁶

IL-6 and cancer stem-like cells

Cancer stem-like cells (CSCs) are specific cells with stem-like properties in cancer cell population. In addition to being possible crucial initiators of cancers, CSCs also enhance the proliferation and invasion of tumor cells and exhibit resistance to conventional antitumor therapies.^97–102 IL-6 has been referred to have an effect on the biological characteristics of CSCs. Activation of IL-6-STAT3 pathway was involved in the growth and survival of glioma stem cells (GSCs), which indicated poor outcome for glioblastoma patients.¹⁰³ IL-6 receptors (IL6-R and gp130) and ligand showed aberrant expression patterns in GSCs, suggesting that IL-6 could regulate GSCs in both autocrine and paracrine ways.¹⁰³ Targeting IL-6R or IL-6 with antibody or shRNA interfered the maintenance and vitality of GSCs in vitro and in vivo.¹⁰³ Krishnamurthy et al.¹⁰⁴ have put forward that tumor-associated endothelial cells promoted the survival and self-renewal of CSCs localizing in perivascular niches in patients with HNSCC. In recent research, they found that IL-6 was a crucial mediator in this crosstalk. Endothelial cell–secreted IL-6 enhanced the survival, self-renewal, and invasive potential of HNSCC CSCs via activating STAT3 in a time-dependent manner in vitro.¹⁰⁵ Moreover, in xenograft mouse model, IL-6 also exhibited a vital role in the tumorigenesis of CSCs, and suppression of IL-6 led to a pronounced decrease in the proportion of CSCs.¹⁰⁵ It has been suggested that the IL-6/JAK/STAT3 pathway was preferentially activated and involved in the growth and survival of stem cell–like breast cancer cells in vitro.^106,107

Interestingly, EMT was reported to be associated with the generation of CSCs in immortalized human mammary epithelial cells, breast cancer cells, and hepatoma cells.^108–111 Xie et al.¹¹² proved that CD44⁺ cells with stem-like characteristics stimulated by IL-6/STAT3 also underwent the process of EMT in the epithelial-like T47D breast cancer cells. It indicated that IL-6 might stimulate the generation and maintenance of functional BrCSCs through EMT process, but the explicit mechanisms are still to be determined.

In a recent study, CSCs were identified as critical targets for MDSCs to establish metastasis in the context of breast cancer. MDSCs-derived IL-6 and NO cooperatively activated STAT3 and NOTCH, which supported continuously induction of breast CSCs.¹¹³ The cancer stemness stimulated by MDSCs was conducive to facilitate tumorigenesis, metastasis, and immune escaping which led to poor prognosis in patients with breast cancer.¹¹³ It is tempting to speculate that a complex reciprocal chemokinetic network may exist in tumor microenvironment. CSCs, as a population of the precursors, endow tumor cells with malignant potentials. IL-6 secreted by endothelial cells in tumor-derived neovascular or MDSCs interacts with IL-6R expressed on CSCs to contribute to the generation of CSCs pool, as well as enhance CSCs properties to stimulate invasion and immunosuppression of tumor cells. Targeted one of the elements in this loop may provide promising therapeutic strategies for tumor in the future.

Targeted-IL-6 immunotherapies

Anti-IL6 antibodies

BE-8, a murine anti-IL-6 monoclonal antibody, was investigated in earlier clinical trials. But unsatisfying results were obtained owing to human anti-murine responses and the shorter half-life of BE-8 (3–4 days).¹² After that, a human-murine anti-IL-6 monoclonal antibody, Siltuximab (CNTO 328), with a long half-time (about 2 weeks) and a human IgG1 region to avoid serious immunogenicity, was applied in preclinical and clinical trials ranging from Castleman’s disease to prostate cancer.^114–119 In recent 5 years, siltuximab was involved in 13 oncological clinical trials listed as active at Clinical Trials Registry (www.clinicaltrials.gov). The safety, effectiveness, and tolerance of siltuximab were assessed in eight phase I and II studies in patients with newly diagnosed or relapsed or refractory multiple myeloma (MM). Among them, a phase II study, containing 106 patients who were newly diagnosed with MM and randomly received nine cycles of bortezomib–melphalan–prednisone (VMP) alone or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance, suggested that the combination of siltuximab with VMP regimen did not significantly improve the complete response (CR) rate (S + VMP: 27%, VMP: 22%) or overall response rate (S + VMP: 88%, VMP: 80%).¹²⁰ The addition of siltuximab to bortezomib in patients with relapsed or refractory MM showed no improvement in progression-free survival (PFS) or overall survival (OS) compared with placebo + bortezomib, despite a numerical increase in response rate in a certain extent.¹²¹ Another three open label phase I/II studies enrolling patients diagnosed with advanced hormone-refractory prostate cancer were conducted to evaluate the safety and efficacy profile of siltuximab as monotherapy or combination therapy. It revealed that siltuximab had favorable tolerance and resulted in a 3.7% prostate-specific antigen (PSA) response rate (RR) and 21% RECIST stable disease rate.¹²²

CNTO136, ALD518, and mAb 1339 are also characterized as targeted biological anti-IL-6 agents. At the beginning, CNTO 136 and ALD 518 were introduced to clinical trials in patients with autoimmune disease, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).¹²³ But only ALD518 showed well-tolerated and alleviated NSCLC-associated anemia and cachexia in both preclinical and clinical trials.¹²⁴ Another promising anti-IL6 agent, mAb 1339, either been used alone or in combination with other agents, exhibited in vitro and in vivo efficacy against MM.^125,126

Anti-IL-6R antibodies

Tocilizumab, a humanized anti-IL-6R monoclonal antibody, blocks both sIL-6R and membrane-bound IL-6R, thus inhibits both classic signaling and trans-signaling. In the last decade, tocilizumab has already been approved for the treatment of Castleman’s disease, RA, systemic-onset, and polyarticular-course juvenile idiopathic arthritis.^127–129 Besides potential roles of tocilizumab in IL-6-driven autoimmune and chronic inflammatory diseases, promising effects on malignant diseases such as ovarian cancer, oral cancer, glioma, MM, and mesothelioma were also found.¹³⁰

In 2016, there were six clinical trials listed as not yet recruiting, recruiting, or completed at www.clinicaltrials.gov about the utilization of tocilizumab in cancer patients. A completed phase I trial evaluated the feasibility, safety, and immunoenhancement of the combination of chemotherapeutics (Carbo/Caelyx or doxorubicin), blockade of IL-6R (tocilizumab), and immune enhancer interferon-α (Peg-Intron) in patients with recurrent epithelial ovarian cancer (EOC). It showed that the addition of tocilizumab in carboplatin/pegylated liposomal doxorubicin (PLD) was feasible and safe in EOC patients.¹³¹ And highest dosage of tocilizumab (8 mg/kg) effectively blocked IL-6R with increased levels of serum IL-6 (p = 0.02) and soluble IL-6R (p = 0.008).¹³¹ Interestingly, the EOC patients with a significant increase in sIL-6R showed a longer median OS time (p = 0.03).¹³¹ The obstruction between IL-6R and IL-6 contributed to decreased pSTAT3 in immune cells, increased IL-12 and IL-1β produced by myeloid cells, and larger quantities of immunological cytokines (IFN-γ and TNF-α) secreted by activated T-cell.

General anti-IL-6 agents

Some chemical agents, such as corticosteroids, NSAIDs, and statins, exert inhibitory effect on IL-6 by controlling its expression through blocking NF-κB. Those agents were widely applied as adjuvant or synergistic drug in amounts of malignancies. Dexamethasone was investigated to suppress the growth of MM partly via the inhibition of IL-6 production and had the potential to be used in hormone-refractory prostate cancer and advanced renal cell carcinoma therapy.^132–134 Even so, the serious side effects of corticosteroids lead to its limitations in therapeutic use. NSAIDs, particularly aspirin, were mostly introduced to prevent or treat various kinds of cancers. Usage of NSAIDs on a regular basis decreased the risk of breast cancer via modifying the IL-6 genotype and of ovarian cancer via promoting apoptosis and restraining angiogenesis.^135,136 NSAIDs also enhanced antitumor immunity by inhibiting IL-6 in human hepatocellular and oral squamous cell carcinoma.^137,138 Simvastatin, as a member of statins, was revealed to inhibit tumor growth and metastasis by suppressing the phosphorylation of JAK2/STAT3 activated by IL-6 in renal cell carcinoma.¹³⁹

Conclusion

To date, IL-6 and its related signal pathways have been well defined. Elevated level of IL-6 in various malignancies is involved in tumor growth and metastasis, thus inducing to a higher tumor burden which includes advanced tumor stage, shortened survival, and earlier recurrence. Notably, IL-6 is associated with chemo-resistance which is one of the most difficult impediments to cure cancer via inhibiting the immune responses and promoting the immune escaping of tumor cells. Based on its roles in immune-modulating, IL-6 can alter the tumor microenvironment toward immunosuppression by attracting and activating associated factors, such as MDSCs, TANs, Tregs, and CSCs. And the schematic diagram showed an immunosuppressive network centered on IL-6 in tumor microenvironment in Figure 2. Therefore, targeted inhibitor of IL-6 has become a crucial class of antitumor drugs in recent years. More and more preclinical and clinical trials have been conducted to evaluate the availability of anti-IL-6 agents in cancers. It may offer molecular targeted therapeutic strategies to sensitize tumor cells to chemotherapy and eventually improve the prognosis of patients with malignancies. It is also remarkable that blockage of IL-6 transduction pathways may be potentially useful in clinical therapy. Nevertheless, the dosage and side effects of anti-IL-6 agents, and whether they can be used alone or in combination with conventional chemotherapy, must be investigated in the future.

Figure 2.

Immune resistance caused by IL-6 within tumor microenvironment. MDSCs and TANs can be chemoattracted to tumor nests by IL-6 from peripheral circulation and contribute to immunosuppression. Attracted MDSCs differentiate into TAMs in tumor nests. IL-6 secreted by tumor cells and MDSCs binds to IL-6R expressed on the surface of above two cells to present both autocrine and paracrine manners. Endothelial cells of tumor-derived neovascularization also express IL-6, which interacted with the IL-6R on CSCs to result in the generation of CSC pool and maintain the CSC properties.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This review was supported by National Natural Science Foundation of China (Grant No. 81572608) and the National High Technology Research and Development Program of China (Grant No. 2015AA020301).

References

Coussens

Werb

. Inflammation and cancer. Nature 2002; 420: 860–867.

Sun

Wang

Zhao

. The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol 2014; 7: 14.

Filipazzi

Huber

Rivoltini

. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 2012; 61: 255–263.

Bunt

Sinha

Clements

. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 2006; 176: 284–290.

Yang

Mortenson

. Targeting and utilizing primary tumors as live vaccines: changing strategies. Cell Mol Immunol 2012; 9: 20–26.

Koebel

Vermi

Swann

. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450: 903–907.

Liu

. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol 2017; 10: 78.

Medina-Echeverz

Aranda

Berraondo

. Myeloid-derived cells are key targets of tumor immunotherapy. Oncoimmunology 2014; 3: e28398.

Biswas

Mantovani

. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11: 889–896.

10.

Bindea

Mlecnik

Tosolini

. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 2013; 39: 782–795.

11.

Park

Richards

McMillan

. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol 2014; 25: 644–651.

12.

Guo

. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 2012; 38: 904–910.

13.

Chen

Jiao

. The endogenous cell-fate factor dachshund restrains prostate epithelial cell migration via repression of cytokine secretion via a CXCL signaling module. Cancer Res 2015; 75: 1992–2004.

14.

Wang

Zhu

. Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFkappaB-TLR signaling pathway. J Hematol Oncol 2016; 9: 42.

15.

Liu

Zhang

Frey

. Prostate-specific IL-6 transgene autonomously induce prostate neoplasm through amplifying inflammation in the prostate and peri-prostatic adipose tissue. J Hematol Oncol 2017; 10: 14.

16.

Naka

Nishimoto

Kishimoto

. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002; 4 Suppl 3: S233–242.

17.

Guthrie

Roxburgh

Richards

. Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer. Br J Cancer 2013; 109: 131–137.

18.

Taniguchi

Karin

. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014; 26: 54–74.

19.

Thomas

Snowden

Zeidler

. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer 2015; 113: 365–371.

20.

O’Shea

Plenge

. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012; 36: 542–550.

21.

Roxburgh

McMillan

. Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer. Transl Res 2016; 167: 61–66.

22.

Kishimoto

. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther 2006; 8 Suppl 2: S2.

23.

Somers

Stahl

Seehra

.1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling. EMBO J 1997; 16: 989–997.

24.

Heinrich

Behrmann

Muller-Newen

. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334(Pt 2): 297–314.

25.

Shimizu

Mitomo

Watanabe

. Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol 1990; 10: 561–568.

26.

Fong

Moldawer

Marano

. Endotoxemia elicits increased circulating beta 2-IFN/IL-6 in man. J Immunol 1989; 142: 2321–2324.

27.

Kohase

May

Tamm

. A cytokine network in human diploid fibroblasts: interactions of beta-interferons, tumor necrosis factor, platelet-derived growth factor, and interleukin-1. Mol Cell Biol 1987; 7: 273–280.

28.

Neurath

Finotto

. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 2011; 22: 83–89.

29.

Tartour

Pere

Maillere

. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 2011; 30: 83–95.

30.

Scheller

Chalaris

Schmidt-Arras

. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 2011; 1813: 878–888.

31.

Chalaris

Garbers

Rabe

. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol 2011; 90: 484–494.

32.

Honda

Yamamoto

Cheng

. Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. J Immunol 1992; 148: 2175–2180.

33.

Rose-John

Heinrich

. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 1994; 300(Pt 2): 281–290.

34.

Rose-John

. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 2012; 8: 1237–1247.

35.

Garbers

Hermanns

Schaper

. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev 2012; 23: 85–97.

36.

Tenhumberg

Waetzig

Chalaris

. Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130. J Biol Chem 2008; 283: 27200–27207.

37.

Jones

Scheller

Rose-John

. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011; 121: 3375–3383.

38.

Waetzig

Rose-John

. Hitting a complex target: an update on interleukin-6 trans-signalling. Expert Opin Ther Targets 2012; 16: 225–236.

39.

Heinrich

Behrmann

Haan

. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003; 374: 1–20.

40.

Imada

Leonard

. The Jak-STAT pathway. Mol Immunol 2000; 37: 1–11.

41.

Levy

Lee

. What does Stat3 do? J Clin Invest 2002; 109: 1143–1148.

42.

Darnell

Jr.

STATs and gene regulation. Science 1997; 277: 1630–1635.

43.

Jove

. The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105.

44.

Sun

Jaruga

Kulkarni

. IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1: regulation by SOCS3. Biochem Biophys Res Commun 2005; 338: 1943–1949.

45.

Nakajima

Kinoshita

Sasagawa

. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci U S A 1993; 90: 2207–2211.

46.

Colombatti

Grasso

Porzia

. The prostate specific membrane antigen regulates the expression of IL-6 and CCL5 in prostate tumour cells by activating the MAPK pathways. PLoS ONE 2009; 4: e4608.

47.

Hennessy

Smith

Ram

. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4: 988–1004.

48.

Chien

Lin

. Naphtho[1,2-b]furan-4,5-dione induces apoptosis of oral squamous cell carcinoma: involvement of EGF receptor/PI3K/Akt signaling pathway. Eur J Pharmacol 2010; 636: 52–58.

49.

Hsu

Shi

Frost

. Interleukin-6 activates phosphoinositol-3′ kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. Oncogene 2004; 23: 3368–3375.

50.

Dienz

Eaton

Bond

. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J Exp Med 2009; 206: 69–78.

51.

Kimura

Kishimoto

. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010; 40: 1830–1835.

52.

El Shikh

El Sayed

. IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation. Int Immunol 2009; 21: 745–756.

53.

Bettelli

Carrier

Gao

. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.

54.

Mangan

Harrington

O’Quinn

. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006; 441: 231–234.

55.

Korn

Bettelli

Oukka

. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485–517.

56.

Camporeale

Poli

. IL-6, IL-17 and STAT3: a holy trinity in auto-immunity? Front Biosci 2012; 17: 2306–2326.

57.

Wing

Sakaguchi

. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 2010; 11: 7–13.

58.

Zhang

Chen

. Inhibition of the interleukin-6 signaling pathway: a strategy to induce immune tolerance. Clin Rev Allergy Immunol 2014; 47: 163–173.

59.

Kitamura

Kamon

Sawa

. IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells. Immunity 2005; 23: 491–502.

60.

Ohno

Kitamura

Takahashi

. IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells. Cancer Immunol Immunother 2016; 65: 193–204.

61.

Narita

Kitamura

Wakita

. The key role of IL-6-arginase cascade for inducing dendritic cell-dependent CD4(+) T cell dysfunction in tumor-bearing mice. J Immunol 2013; 190: 812–820.

62.

Sumida

Wakita

Narita

. Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses. Eur J Immunol 2012; 42: 2060–2072.

63.

Srivastava

Sinha

Clements

. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 2010; 70: 68–77.

64.

Gabrilovich

Nagaraj

. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009; 9: 162–174.

65.

Rodriguez

Quiceno

Zabaleta

. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 2004; 64: 5839–5849.

66.

Yan

. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol 2013; 190: 3783–3797.

67.

Sinha

Clements

Bunt

. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 2007; 179: 977–983.

68.

Liu

Tian

. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev 2016; 31: 61–71.

69.

Kusmartsev

Gabrilovich

. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 2005; 174: 4880–4891.

70.

Diaz-Montero

Salem

Nishimura

. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009; 58: 49–59.

71.

Bunt

Yang

Sinha

. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 2007; 67: 10019–10026.

72.

Kusmartsev

Gabrilovich

. Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother 2002; 51: 293–298.

73.

Nefedova

Huang

Kusmartsev

. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 2004; 172: 464–474.

74.

Zhao

Song

. Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp Cell Res 2017; 351: 142–149.

75.

Chen

Kuan

Yen

. IL-6-stimulated CD11b+ CD14+ HLA-DR- myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus. Oncotarget 2014; 5: 8716–8728.

76.

Medzhitov

Shevach

Trinchieri

. Highlights of 10 years of immunology in nature reviews immunology. Nat Rev Immunol 2011; 11: 693–702.

77.

Wang

Yan

. Noncanonical NF-κB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer. J Immunol 2014; 193: 2574–2586.

78.

Di Carlo

Forni

Lollini

. The intriguing role of polymorphonuclear neutrophils in antitumor reactions. Blood 2001; 97: 339–345.

79.

Rao

Chen

. Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS ONE 2012; 7: e30806.

80.

Wang

Jia

Wang

. The clinical significance of tumor-infiltrating neutrophils and neutrophil-to-CD8+ lymphocyte ratio in patients with resectable esophageal squamous cell carcinoma. J Transl Med 2014; 12: 7.

81.

Tazzyman

Lewis

Murdoch

. Neutrophils: key mediators of tumour angiogenesis. Int J Exp Pathol 2009; 90: 222–231.

82.

Houghton

. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 2010; 9: 1732–1737.

83.

Yan

Wei

Yuan

. IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation. J Immunol 2013; 190: 5882–5893.

84.

Zhu

Zhang

. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death Dis 2014; 5: e1295.

85.

Thiery

. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003; 15: 740–746.

86.

Lee

Dedhar

Kalluri

. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 2006; 172: 973–981.

87.

Vandewalle

Comijn

De Craene

. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res 2005; 33: 6566–6578.

88.

Sullivan

Sasser

Axel

. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 2009; 28: 2940–2947.

89.

Sasser

Sullivan

Studebaker

. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J 2007; 21: 3763–3770.

90.

Cheng

Zhang

Sun

. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem 2008; 283: 14665–14673.

91.

Chung

Parker

Ely

. Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res 2006; 66: 8210–8218.

92.

Yadav

Kumar

Datta

. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 2011; 9: 1658–1667.

93.

Miao

Liu

Huang

. Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma. Int J Oncol 2014; 45: 165–176.

94.

Sun

Zhang

Wang

. Shp2 plays a critical role in IL-6-induced EMT in breast cancer cells. Int J Mol Sci 2017; 18: E395.

95.

Han

Xiao

. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res 2014; 20: 2714–2726.

96.

Zhao

Yao

. Wogonin suppresses human alveolar adenocarcinoma cell A549 migration in inflammatory microenvironment by modulating the IL-6/STAT3 signaling pathway. Mol Carcinog 2015; 54 (Suppl. 1): E81–E93.

97.

Ailles

Weissman

. Cancer stem cells in solid tumors. Curr Opin Biotechnol 2007; 18: 460–466.

98.

Rosen

Jordan

. The increasing complexity of the cancer stem cell paradigm. Science 2009; 324: 1670–1673.

99.

Shackleton

Quintana

Fearon

. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 2009; 138: 822–829.

100.

Al-Ejeh

Smart

Morrison

. Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis 2011; 32: 650–658.

101.

Schulenburg

Blatt

Cerny-Reiterer

. Cancer stem cells in basic science and in translational oncology: can we translate into clinical application? J Hematol Oncol 2015; 8: 16.

102.

Tian

. CD44 correlates with clinicopathological characteristics and is upregulated by EGFR in breast cancer. Int J Oncol 2016; 49: 1343–1350.

103.

Wang

Lathia

. Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 2009; 27: 2393–2404.

104.

Krishnamurthy

Dong

Vodopyanov

. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res 2010; 70: 9969–9978.

105.

Krishnamurthy

Warner

Dong

. Endothelial interleukin-6 defines the tumorigenic potential of primary human cancer stem cells. Stem Cells 2014; 32: 2845–2857.

106.

Marotta

Almendro

Marusyk

. The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors. J Clin Invest 2011; 121: 2723–2735.

107.

Berishaj

Gao

Ahmed

. Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res 2007; 9: R32.

108.

Morel

Lievre

Thomas

. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 2008; 3: e2888.

109.

Mani

Guo

Liao

. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

110.

Jayachandran

Dhungel

Steel

. Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma. J Hematol Oncol 2016; 9: 74.

111.

Tian

Yuan

. Enrichment of CD44 in basal-type breast cancer correlates with EMT, cancer stem cell gene profile, and prognosis. Onco Targets Ther 2016; 9: 431–444.

112.

Xie

Yao

Liu

. IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures. Int J Oncol 2012; 40: 1171–1179.

113.

Peng

Tanikawa

. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res 2016; 76: 3156–3165.

114.

Puchalski

Prabhakar

Jiao

. Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. Clin Cancer Res 2010; 16: 1652–1661.

115.

Coward

Kulbe

Chakravarty

. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res 2011; 17: 6083–6096.

116.

Rossi

Negrier

James

. A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer. Br J Cancer 2010; 103: 1154–1162.

117.

Karkera

Steiner

. The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate 2011; 71: 1455–1465.

118.

Fizazi

De Bono

Flechon

. Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 2012; 48: 85–93.

119.

Van Rhee

Fayad

Voorhees

. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol 2010; 28: 3701–3708.

120.

San-Miguel

Blade

Shpilberg

. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2014; 123: 4136–4142.

121.

Orlowski

Gercheva

Williams

. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol 2015; 90: 42–49.

122.

Dorff

Goldman

Pinski

. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res 2010; 16: 3028–3034.

123.

Kopf

Bachmann

Marsland

. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov 2010; 9: 703–718.

124.

Bayliss

Smith

Schuster

. A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin Biol Ther 2011; 11: 1663–1668.

125.

Ara

Declerck

. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 2010; 46: 1223–1231.

126.

Ataie-Kachoie

Pourgholami

Morris

. Inhibition of the IL-6 signaling pathway: a strategy to combat chronic inflammatory diseases and cancer. Cytokine Growth Factor Rev 2013; 24: 163–173.

127.

Venkiteshwaran

. Tocilizumab. MAbs 2009; 1: 432–438.

128.

Makol

Gibson

Michet

. Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutaneous lupus and urticarial vasculitis. J Clin Rheumatol 2012; 18: 92–95.

129.

Nagao

Nakazawa

Hanabusa

. Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases. J Hematol Oncol 2014; 7: 10.

130.

Uemura

Trinh

Haymaker

. Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn’s disease: a case report. J Hematol Oncol 2016; 9: 81.

131.

Dijkgraaf

Santegoets

Reyners

. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-α2b in patients with recurrent epithelial ovarian cancer. Ann Oncol 2015; 26: 2141–2149.

132.

Miyake

Fujisawa

. Molecular-targeted therapy for prostate cancer. Nihon Rinsho 2016; 74: 2–5.

133.

Arai

Nonomura

Nakai

. The growth-inhibitory effects of dexamethasone on renal cell carcinoma in vivo and in vitro. Cancer Invest 2008; 26: 35–40.

134.

Morgan

. Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies. Blood Rev 2010; 24 (Suppl. 1): S27–S32.

135.

Zerbini

Tamura

Correa

. Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-κΒ inhibitors in ovarian cancer therapy. PLoS ONE 2011; 6: e24285.

136.

Slattery

Curtin

Baumgartner

. IL6, aspirin, nonsteroidal anti-inflammatory drugs, and breast cancer risk in women living in the southwestern United States. Cancer Epidemiol Biomarkers Prev 2007; 16: 747–755.

137.

Liu

. Celecoxib inhibits interleukin-6/interleukin-6 receptor-induced JAK2/STAT3 phosphorylation in human hepatocellular carcinoma cells. Cancer Prev Res 2011; 4: 1296–1305.

138.

Nikitakis

Hamburger

Sauk

. The nonsteroidal anti-inflammatory drug sulindac causes down-regulation of signal transducer and activator of transcription 3 in human oral squamous cell carcinoma cells. Cancer Res 2002; 62: 1004–1007.

139.

Fang

Tang

Fang

. Simvastatin inhibits renal cancer cell growth and metastasis via AKT/mTOR, ERK and JAK2/STAT3 pathway. PLoS ONE 2013; 8: e62823.

Targeting interlukin-6 to relieve immunosuppression in tumor microenvironment

Abstract

Keywords

Introduction

Structure and intracellular signaling pathways of IL-6

The double effects of IL-6 on immunoregulation

Interaction between IL-6 and immune resistance in tumor microenvironment

IL-6 and MDSCs

IL-6 and TANs

IL-6 and epithelial–mesenchymal transition

The positive correlation between IL-6 and EMT

IL-6 and cancer stem-like cells

Targeted-IL-6 immunotherapies

Anti-IL6 antibodies

Anti-IL-6R antibodies

General anti-IL-6 agents

Conclusion

Footnotes

Declaration of conflicting interests

Funding

References