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Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18 Interleukin-18 (IL-18) is an immune-stimulatory cytokine with antitumor activity in preclinical models. It plays pivotal roles in linking inflammatory immune responses and tumor progression and is a useful candidate in gene therapy of lymphoma or lymphoid leukemia. A phase I study of recombinant human IL-18 (rhIL-18) in patients with advanced cancer concluded that rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. Some viruses can induce the secretion of IL-18 for immune evasion. The individual cytokine activity might be potentiated or inhibited by combinations of cytokines. Here we focus on combinational effects of cytokines with IL-18 in cancer progression. IL-18 is an important non- invasive marker suspected of contributing to metastasis. Serum IL-18 may a useful biological marker as independent prognostic factor of survival. In this review we cover roles of IL-18 in immune evasion, metastasis and angiogenesis, applications for chemotherapy and prognostic or diagnostic significance. Keywords: Interleukin-18 - cancer - angiogenesis - immunotherapy - predictive marker Asian Pacific J Cancer Prev, 13 (11), 5353-5361 (Michael et al., 2008). IL-18 is a useful candidate gene Immuno Therapeutics in gene therapy of lymphoma or lymphoid leukemia. Immunotherapy is defined as the “treatment of (Zhang et al., 2004). The combination of IL-18 and IL-2 disease by inducing, enhancing, or suppressing an is considered a viable strategy to induce an antitumor immune response”. Immunotherapies designed to elicit or response in vivo (Young et al., 2001). Plasma levels amplify an immune response are classified as activation and mRNA levels of IL-18 and its converting enzyme, immunotherapies. Cytokines are small cell-signaling caspase-1, were significantly elevated in Cutaneous T-cell protein molecules that are secreted by the immune system lymphoma (Kei-ichi et al., 2006). and used extensively in intercellular communication. IL-18 plays pivotal roles in linking inflammatory IL-18 viral infections immune responses and tumor progression. It is a pro- Epstein-Barr virus (EBV) latently infects and inflammatory cytokine converted to a biologically active immortalizes B lymphocytes and causes lympho molecule by IL-1beta converting enzyme (caspase-1). proliferative malignancies. EBV nuclear antigen EBNA2 IL-18 has various biological activities after its secretion induces expression of the 2 chains of the interleukin-18 as an 18 kDa mature form. A wide range of normal and receptor (IL-18R) in Burkitt lymphoma (BL) cell lines cancer cell types can produce and respond to IL-18 through and in non-transformed B cells. EBNA2 expression is a specific receptor (IL-18R) belonging to the toll-like associated with IL-18R expression in vivo in EBV-positive receptor family. The activity of IL-18 is regulated by IL- B-lymphomas from AIDS patients (Franck et al., 2005). 18-binding protein (IL-18bp), a secreted protein possessing IL-18 expression in response to a viral latency protein the ability to neutralize IL-18. It stimulates natural killer and suggest that IL-18 may play an important role as (NK) and T cells and enhances Th1 immune response. It is an endogenous inducer of IFN-g expression, thereby an immune-stimulatory cytokine with antitumor activity in contributing to tumor regression (Lei et al., 2001). IL-18 preclinical models. It increases the serum concentrations binding protein (IL-18BP) is a circulating protein that of IFN-g, granulocyte macrophage colony-stimulating binds IL-18 and neutralizes its activity. IL-18 production is factor and soluble Fas ligand (Robertson et al., 2006). increases in chronic HCV infection. IFN-a administration A phase I study of recombinant human IL-18 (rhIL-18) increased IL-18BP plasma levels 3.24 fold 24 h resulting in in patients with advanced cancer concluded that rhIL-18 a 67.4% reduction of free IL-18. These anti-inflammatory can be safely given in biologically active doses to patients properties might account together with its antiviral action with advanced cancer. The rhIL-18 increases expression for its clinical efficacy in chronic hepatitis C (Kaser et al., of activation antigens on lymphocytes and monocytes 2002). Institute of Genetics and Hospital for Genetic Diseases, Osmania University , Begumpet, Hyderabad, India *For correspondence: hemaprasadm@yahoo.com Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5353 Manohar Babu Kuppala et al a major anti-tumor activity via stimulation of a T-helper IL-18 Effects on Different Cancers type 1 (Th1) and T-helper type 2 (Th2) immune responses. IL-18 is a systemic, multifunctional cytokine with Intra-tumoral cytokine delivery has therapeutic potential both pro-cancerous and anti-cancer activities. There is for immunotherapy of cancers. growing evidence suggesting that IL-18 levels may affect Cytokine expression profiles may depend on type individual to virus-associated neoplasia and that single of cancer. The Th1 cytokines, particularly IL-12, were nucleotide polymorphisms within the gene may influence increased in adjacent mucosa of colorectal adenoma, its production. Variations in the DNA sequence in the IL- but all Th1 cytokines significantly decreased in adjacent 18 gene promoter may lead to altered IL-18 production, mucosa of colorectal carcinoma (Cui et al., 2007). IL-6 and so this can modulate an individual’s susceptibility. concentration increased as the tumor stage progressed, and IL-18 gene promoter polymorphism is reported to be a a significant difference appeared between stage of head genetic risk factor for several types of cancer (Han et al., and neck squamous cell carcinoma patients (Mojtahedi et 2003). al., 2011). IL-18, a cytokine that plays an important role in the IL-18 gene promoter polymorphism T-cell-helper response, acts as an angiogenic factor and Reporter gene assay reveals the significance of SNPs a tumor suppressor. There is a significant difference in of alleles in IL-18 gene promoter in HepG2 and Hep3B the levels of IL-18 between breast cancer patients with cells are associated with the presence of HCC (Kim et metastatic and non-metastatic cases. IL-18 is an important al., 2009). Significant genotype differences in the IL-18 non-invasive marker suspecting metastasis (Eissa et al., promoter region (-607) between the lung cancer patients 2005) Metastatic patients showed significantly higher and controls in Iranian population (Farjadfar et al., 2009). IL-18 mean values with respect to both healthy controls C allele at position -607 was associated with a higher risk and non-metastatic patients (Lissoni et al., 2000). of cirrhosis and HCC (Bouzgarrou et al., 2008). Co-administration of low-dose IL-2 plus IL-18 induced Significant difference in the frequency of -137 G/C a potent primary response to murine neuroblastoma genotype were found in colorectal cancers, nasopharyngeal and activation of natural killer cells in the tumor (Nong et al., 2009), breast cancer (Khalili et al., 2009), microenvironment. mIL-12 and mIL-18 synergistic cervical cancer (Sobti et al., 2008) and prostate cancers effect inhibit tumor angiogenesis (Coughlin et al., 1998). (Liu et al., 2007). Haplotype analysis showed statistical IL-2 plus IL-18cytokine treatment shows complete and significance in patients with stomach cancer -607 C/-137 durable antitumor response (Redlinger et al., 2003). C and -607 A/-137 G and in patients with colorectal cancer Intratumoral treatment with IL-18 and IL-12-encoding and esophageal squamous cell carcinoma (Wei et al., 2007; plasmid DNA has antitumor effects, which is well tolerated Haghshenas et al., 2009). and thus holds promise for the treatment of patients with metastatic melanoma (Muller et al., 2011). Both IL-10 and IL-18 levels in the peritoneal cavity increased with Effect of Combinational Cytokines with IL-18 tumor progression. Peritoneal exudates cells capable on Outcome of Cell Proliferation of producing IFN-gamma in response to IL-18 may be influenced by local IL-10 levels in the peritoneal cavity Different cytokines show dissimilar activities on (Majima et al., 2002). IFN-gamma, IL-15, and IL-18were cancer progression. Cytokines are key players exerting induced in patients treated with rhIL-12. The down- tumor and anti-tumor properties in the biological processes modulation of IFN-gamma induction during rhIL-12 of malignant tumors. The individual cytokine activity treatment did not relate to IL-10 production or alterations might potentiate or inhibited by combination of cytokines. in rhIL-12 bioavailability but was associated with an The relationship between pro-inflammatory and anti- acquired defect in lymphocyte IFN-gamma production inflammatory cytokines are responsible for the presence in response to IL-12, IL-2, or IL-15 (Gollob et al., 2000). and intensity of cancer progression. These cytokines have Table 1. IL-18 Promoter Polymorphism and Association with Cancer Progression in Different Cancers S.No -607 -137 Type of Cancer Patients Vs Association with Cancer out come Reference C/A G/C Control cancer progression 1 C C polycystic ovary syndrome 118 Vs 79 Not Associated Protective role Yang et al., 2010 2 A -- lung cancer 73 Vs 97 Associated cancer risk Farjadfar et al., 2009 3 A G GI cancers 232 Vs 312 Associated Protective role Haghshenas et al., 2009 4 A C Nasopharyngeal 250 Vs 270 Associated cancer risk Nong et al., 2009 5 A C ovarian cancer 85 Vs 158 Not Associated No role Samsami et al., 2009 6 A CC breast cancer 250 Vs 206 Associated Protective role Khalili et al., 2009 7 A C head and neck carcinoma 111 Vs 212 Not Associated No role Asefi et al., 2009 8 C C Cervical cancer 115 Vs 180 Associated Increased Cancer risk Sobti et al., 2008 100.0 9 A -- Nasopharyngeal carcinoma 163 Vs 164 Not Associated Increased cancer risk Farhat et al., 2008 6.3 12.8 10.1 20.3 10 A -- oral cancer 149 Vs 89 Not associated No role Vairaktaris et al., 2007 10.3 11 C -- Esophageal carcinoma 235 Vs 250 Associate Increased risk Wei et al., 2007 25.0 30.0 75.0 12 A C prostate cancer 265 Vs 280 Associate Increased risk Liu et al., 2007 75.0 46.8 56.3 51.1 Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 51.7 54.2 50.0 31.3 30.0 25.0 38.0 33.1 31.3 31.3 30.0 27.6 25.0 23.7 Newly diagnosed without treatment Newly diagnosed with treatment Persistence or recurrence Remission None Chemotherapy Radiotherapy Concurrent chemoradiation DOI:http://dx.doi.org/10.7314/APJCP.2012.13.11.5353 VEGF and IL-18 are markers for transformation of cancer progression and metastasis remains controversial. benign cells to metastatic cancer cells. Concentrations of The regulation of the IL-18 secretion process is an VEGF and IL-18 in the serum are sensitive tumor markers important step in tumor progression. in this patient group before and after treatment. High production of VEGF was associated with low production Il-18 enhances cancer progression of IL-18 (Jablonska et al., 2005). PEG interferon alpha- Chronic inflammation is associated with tumor 2b treatment was associated with decrease in plasma development and progression. IL-18 plays a central role basic fibroblast growth factor and increase in plasma in inflammation and the immune response, contributing interleukin-18. Bevacizumab therapy reduces tumor to the pathogenesis and pathophysiology of infectious and blood flow and resulting anticancer activity. No significant inflammatory diseases. High levels of IL-18 production changes in tumor blood flow were observed following may play a major role in the growth, invasion and PEG interferon (Yao et al., 2008). metastasis of renal cancer (Saenz et al., 2010). Higher Cytokines are responsible for progression of cancers. expression of IL-18 is detected in various cancer cells Serum IL-12 and IL-18 levels were higher in patients with (Park et al., 2007). Patients with high serum IL-18 levels IV stage of esophageal cancer (Diakowska et al., 2006). had a poorer survival than those with low serum IL-18 Intratumoral expressions of IL-12 and IL-18 can play an levels. Serum IL-18 level, but not IL-6 and IL-12 levels, important role in progression and metastasis of gastric was a significant and independent prognostic factor of cancer (Ye et al., 2007). Serum IL-12 and IL-18 levels survival in hepato cellular carcinoma (Tangkiivanich were significantly higher and increased in patients as the et al., 2007). Signaling through the adaptor protein pathologic stage progressed in patients with esophageal myeloid differentiation factor 88 (MyD88) promotes carcinoma. IL-12 and IL-18 levels correlate with a certain carcinogenesis in several cancer models (Salcedo et al., depth of invasion and might be useful tumor markers in 2010). patients with esophageal carcinoma (Tsuboi et al., 2004). Interleukin 18 binding protein (IL-18BP), a potent inhibitor of interleukin 18, significantly up regulated in large volume disease. Elevated IL-18BP secretion Role of IL-18 in Cancer Progression from cancer cells suggests an attempt by cancer to IL-18 is a pleiotropic, pro-inflammatory cytokine plays escape immune surveillance. IL-18BP merits further a critical role in tumor migration, invasion, and metastasis, study as a marker of aggressive prostate cancer and as with dual effects on tumor development and progression. a therapeutic target (Fujita et al., 2011). IL-18 inhibits Immunosuppressive cytokines subvert innate and cancer cell immune surveillance by indirect expression adaptive immune responses during cancer progression. of programmed death-1 gene. IL-18 produced by tumor IL-18 increases the escape immune recognition, increase cells promotes the development of NK-controlled adherence to the microvascular wall and induce production metastases in a PD-1-dependent manner. Accordingly, of angiogenic and tumor growth-stimulating factors via PD-1 is expressed by activated mature NK cells in IL-18-dependent mechanism. Thus, the role of IL-18 in lymphoid organs of tumor bearers and is up regulated by IL-18, as an immunosuppressive cytokine in cancer (Terme et al., 2011). VEGF-D enhanced cell migration Table 2. Effects of Cytokines is blocked by inhibiting IL-18. VEGF-D increased IL-18 S.No Combination Type of Cancer Reference expression and secretion, suggesting that IL-18 is a critical Anti Tumor Activity: mediator for VEGF-D-enhanced migration. VEGF-D 1 IL-12, IL-18 Mammary carcinoma Coughlin et al., 1998 induced a disintegrin and metalloprotease 33 (ADAM33) 2 IL-12, TNF-alpha Breast cancer Sabel et al., 2010 3 IFN-gamma, IL-12 Gastric carcinoma Majima et al., 2002 expression, which has a metalloproteinase domain (Kim 4 IL-10, IL-18 Gastric carcinoma Majima et al., 2002 et al., 2009). IL-18 is an important non-invasive marker 5 IL-2, IL-18 Neuroblastoma Redlinger et al., 2003 suspecting metastasis (Eissa et al., 2005). 6 IL-2, IL-12 Melanoma Muller et al., 2011 7 VEGF, IL-18 Oral cavity cancer Jablonska et al., 2005 Tumor Progression: Mechanism of IL-18 in cancer progression 1 IL-12, IL-18 Eesophageal carcinoma Diakowska et al., 2006 Hypoxia induces the transcription and secretion of IL- 2 IL-12, IL-18 Gastric cancer Sabel et al., 2010 18, which subsequently induces the expression of hypoxia- 3 IL-12, IL-18 Esophageal carcinoma Tsuboi et al., 2004 inducible factor-1alpha (HIF-1alpha). Mechanistically, 4 IL-10, IL-12 Head and neck squamous cell Jebreel et al., 2007 IL-18 induces HIF-1alpha through the activity of the *Anti Tumor Activity S. No (1-6)=Nature: Synergism and S. No GTPase Rac1, which inducibly associates with the IL- (7)=Nature: Antagonism. **Tumor Progression S. No (1-3)=Nature: Synergism and S. No (4)=Nature: Antagonism 18receptor beta (IL-18Rbeta) subunit, via a PI3K-AKT- Table 3. Role of IL-18 in Cancer Progression S. No Activity of IL-18 Angiogenic protein Type of Cancer Reference 1 Angiogenesis Down regulation of filamentous-actin polymerization and tensin Gastric cancer cell lines Kim et al., 2007 2 Angiogenesis alpha(v)beta(3) integrin Micro vascular endothelial cell (HMVEC) Park et al., 2001 3 Anti- angiogenesis Activation of T helper type 1 cells Colon carcinoma Tasaki et al., 2000 4 Tumor suppressor Inhibiting fibroblast growth factor-2 Carcinoma Cao et al., 1999 5 Inhibit immune surveillance expression of programmed death-1 Lymphoid carcinoma Terme et al., 2011 6 Inhibiting VEGF disintegrin and metallo protease 33 (ADAM33) Gastric cancer Kim et al., 2009 7 Metastasis Induction hypoxia-inducible factor-1alpha (HIF-1alpha) Carcinoma Kim et al., 2008 Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5355 Manohar Babu Kuppala et al NF-kappaB-dependent pathway. HIF-1alpha-mediated IL-18R-triggered signaling pathway increased activities of tumor progression, in which the induction of IL-18 by extracellular matrix metalloproteinase (MMP)-9, MMP-3, hypoxia or inflammatory cells augments the expression and MMP-2 by IL-18, which upregulated the mRNA levels of both HIF-1alpha and tumor cell metastasis (Kim et of MMP-3 and MMP-9 in a NF-κB-dependent manner al., 2008). (Zang et al., 2011). IL-18 grow/invade and evade immune surveillance in the hosts. Role of IL-18 in Immune Evasuion Mechanism of immune suppression by IL-18 A strong cell-mediated immune response is critical for Said et al. showed that inflammatory cytokines cause controlling viral infections and is regulated by a number an IL-10-dependent inhibition of CD4 T-cell expansion of cytokines. Large-scale genome studies have found and function by up-regulating PD-1 levels on monocytes correlations between single-nucleotide polymorphisms which leads to IL-10 production by monocytes after (SNPs) in the IL 18 promoter and spontaneous control of binding of PD-1 by PD-L. viral infections. IL-18 has been reported to inhibit hepatitis B virus replication in the liver of HBV transgenic mice. Role of IL-18 in Cancer Metastasis Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon Cancer cells metastasize to the other site after escaping (IFN)-γ by effector and memory CD8 T cells. Orthopox from the immune system and CD70, CD44 and vascular viruses, ectromelia virus, encode immune evasion endothelial growth factor (VEGF) play important roles molecules that specifically target IL-18 and IFN-gamma. in this process. Implantation and growth of metastatic Cancer cells metastasize to the other site after escaping cancer cells at distant organs is promoted by inflammation- from the immune system and vascular endothelial growth dependent mechanisms. factor (VEGF) play important roles in this process. IL-18 is a pro inflammatory cytokine, key marker CD8 T cells produce IFN-γ and upregulate CD25 for matastasis. IL-18 levels suppress CD70 expression following exposure to certain combinations of IL-12, and increases immune susceptibility of cancer cells. IL-18, and IL-21. The unresponsiveness of exhausted Endogenous IL-18 facilitate cancer cell immune escape CD8 T cells is associated with down regulation of the by suppressing CD70 and increasing metastatic ability IL-18-receptor-α (IL-18Rα). Exhausted T cells lose by upregulating CD44 and VEGF (Kang et al., 2009). their susceptibility to antigen-independent activation Expression of IL-18/IL-18R were remarkably up regulates by cytokines, which compromises their ability to detect and triggered signaling pathway related to metastasis in bacterial co-infections (Ingram et al., 2011). Absence hepatocellular carcinoma (Zang et al., 2011). Expression of both IL-12p40 and IL-18 resulted in increased of discoidin domain receptor 2 (DDR2) is essential for susceptibility to infection and reduction in NK and CTL metastatic activity as it is regulate expression of IL-18 in responses. IL-12p40 and IL-18 act in concert and play an hepatic stellate cells (HSC). DDR2 deficiency in HSCs important antiviral role through the up-regulation of IFN- led to decreased gene expression of interleukin IL-18 and gamma production and cell-mediated immune responses insulin-like growth factor-I; and increased gene expression (Wang et al., 2009). Post transplant lympho proliferative of prometastatic factors IL-10, transforming growth disease tissues express significantly lower levels of IL- factor (TGF)β and vascular endothelial growth factor 18 and interferon-gamma permitting the uncontrolled (VEGF) (Badiola et al., 2011). Erythroid differentiation expansion of Epstein-Barr virus (EBV)-infected B regulator (Erdr1) is a stress-related survival factor. The lymphocytes, compared to lymphoid tissues diagnosed expression of Erdr1 is negatively correlated with IL-18 with acute EBV-induced infectious mononucleosis expression. Erdr1 over expression markedly inhibited (Setsuda et al., 1999). the level of cell migration, invasion, and proliferation in IL-18, can enhance Fas ligand expression and suppress B16F10 cells in vitro (Jung et al., 2011). Selenium can the immune system (Cho et al., 2000). Cancer cells prevent metastasis by inhibiting IL-18 gene expression escape immune response by IL-18 and IL-18 receptors in a dose-dependent manner. Selenium might be a potent expression. IL-18 dose-dependently enhances proliferation inhibitor of the metastatic capacity of melanoma cells, via accompanied by nuclear factor kappaB activation. IL-18- down-modulation of IL-18 expression (Song et al., 2011). pretreated gastric cancer cells, decreased susceptibility to IL-1 gene is frequently expressed in metastases from perforin or interferon-gamma production (Majima et al., patients with several types of human cancers. IL-1Ra 2006). IL-18 plays a key role in regulating the immune escape by production of Thrombospondin (TSP-1). TSP-1 is known to inhibit angiogenesis in several cancers. IL-18 enhanced the expression of phosphorylated JNK. Overall, these results suggest that IL-18 plays a key role in TSP-1 expression involving JNK (Kim et al., 2006). Endogenous IL-18 facilitate cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF (Kang et al., 2009). IL-18 show dual effects on inhibition HBV replication and promotion of Figure 1. Mechanism of Immune Suppression by IL-18 metastasis and migration in human hepatocytes. IL-18/ Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5356 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.11.5353 inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers (Elaraj et al., 2006). Resveratrol is anti inflammatory drug remarkably inhibited hepatic retention and metastatic growth of melanoma cells. The mechanism involved IL-18 blockade by resveratrol prevented IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature and inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells (Salado et al., 2011). Furthermore, IL-   18-induced C6 migration and microfilament disassembly Figure 2. Mechanism of IL-18 in Angiogenesis by were antagonized by iNOS inhibitor, guanylate cyclase Different Pathways. IL-18; Interleukin-18, MCP-1; (GC) inhibitor and protein kinase G (PKG) inhibitor. monocyte chemoattractant protein 1, SDF-1alpha; stromal cell- derived factor 1alpha, PKCdelta; protein kinase Cdelta, PI3K; IL-18 secreted by microglia, enhanced migration of C6 phosphatidylinositol 3-kinase, ATF-2; activating transcription glioma through NO/cGMP pathway (Yen et al., 2011). factor 2 Serum IL-18 negatively associated with overall survival in small cell lung cancer (NSCLC). Serum IL-18 levels MAPK, and activating transcription factor 2 (ATF-2) in were significantly higher in NSCLC with metastasis than fibroblasts in a time-dependent manner, with JNK-2 being in NSCLC without metastasis (Okamoto et al., 2009). upstream of PKCdelta, ATF-2, and NFkappaB. IL-18 has a unique role in inducing the secretion of angiogenic Role of IL-18 in Angiogenesis SDF-1alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates (Amin Cell migration and angiogenesis are key steps in tumor et al., 2007). metastasis. The relationship between pro-angiogenic and anti-angiogenic factors is responsible for the presence and IL-18 enhances angiogenesis intensity of neoangiogenesis. IL-18, a cytokine belonging IL-18 is associated with the induction of angiogenic to the IL-1 family, and is potent cytokine that induces the factors, migration and malignant progression of tumors. neo vascularization. IL-18 also called interferon-gamma Inhibiting IL-18 markedly reduced the level of Vascular (IFN-gamma)-inducing factor, has been characterized endothelial growth factor (VEGF)-enhanced migration, as a potent IFN-gamma-inducing cytokine. IL-18 is a and IL-18 increases cell migration directly through highly regulated inflammatory cytokine that is elevated filamentous-actin polymerization and tensin down in synovial tissues and synovial fluids of patients with regulation (Kim et al., 2007). Human IL-18 induces micro rheumatoid arthritis (RA). IL-18 induces endothelial cell vascular endothelial cell (HMVEC) migration. IL-18 migration and angiogenesis by binding and activating appears to act on HMVECs via alpha(v)beta(3) integrin. endothelial cells and indirectly by vascular endothelial The angiogenesis is independent of the contribution of growth factor. IL-18 mediates all these inflammatory local TNF-alpha. Down-regulation of IL-18 activity or processes by binding to its receptor, IL-18 receptor, and AP-1 signal pathway can be potential therapeutic targets initiating the activation of different signaling cascades for rheumatoid arthritis. VEGF plays an important leading to changes in target cells gene expression and role in angiogenesis in rheumatoid synoviocytes (Cho behavior. IL-12 and IL-18 play an important role as et al., 2006). Microvascular abnormalities are one immunomodulatory factors in cancer pathogenesis (Volin of the most important causes of persistent diabetic et al., 2011). complications. Higher serum levels of sE-selectin and IL-18 were demonstrated in diabetic patients compared Mechanisms of IL-18 in angiogenesis to controls. Significant differences of sE-selectin and IL- IL-18 significantly enhanced the production of stromal 18 serum concentrations were observed between diabetic cell-derived factor 1alpha (SDF-1alpha)/CXCL12, patients with microangiopathy and controls suggest that monocyte chemoattractant protein 1 (MCP-1)/CCL2, and abnormalities in nailfold capillaroscopy may reflect the vascular endothelial growth factor (VEGF). IL-18-induced extent of microvascular involvement and are associated SDF-1alpha/CXCL12 up-regulation was dependent on with higher sE-selectin and IL-18 serum levels, as well JNK, p38 MAPK, phosphatidylinositol 3-kinase (PI3K), as with microangiopathic complications in diabetic and NFkappaB. IL-18-induced production of SDF-1alpha/ patients (Kuryliszyn et al., 2011). Hyper glycaemia CXCL12 was also dependent on protein kinase Cdelta increases inflammatory cytokine concentration in the (PKCdelta), production of MCP-1/CCL2 was dependent blood. Elevated levels of IL-18, in patients with Type 2 on PKCalpha, not PKCdelta. IL-18-induced MCP-1/CCL2 diabetes mellitus (DM2) and nephropathy. Recombinant production was mediated by JNK, PI3K, and NFkappaB. human IL-18 injected intra dermally to murine skin IL-18 induced phosphorylation of JNK, PKCdelta, p38 Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5357 Manohar Babu Kuppala et al induced significant neovascular reaction. DM2 patients of the metastatic capacity of melanoma cells, via down- sera contained higher concentration of IL-18 and induced modulation of IL-18 expression (Song et al., 2011). stronger neovascular reaction in mice skin than did the sera High levels of interleukin (IL)-12 and IL-18 were of corresponding control people (Skopinski et al., 2005). associated with a sustained virological response. IL-18 regulates pathogenic retinal neovascularization Conversely, high baseline IL-10 levels were significantly by promoting its regression rather than inhibiting its associated with a nonresponse to treatment. In multivariate development in an oxygen-induced retinopathy and is a analysis, low IL-10, high IL-12, and high IL-18 levels useful, new approach to treating retinopathy in humans were independently associated with an SVR. Serum IL- (Qiao et al., 2007). 10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin (Yoneda et al., 2011). Methicillin-resistant Staphylococcus IL-18 and Chemotherapy aureus (MRSA) infection is a grave concern in burn- Resistance to chemotherapy is the major cause of failure injured patients. IL-18 treatment increased the serum in cancer treatment. Time-dependent chemotherapeutic tumor necrosis factor (TNF), IL-17, IL-23, granulocyte agents can selectively target tumor cells in susceptible colony-stimulating factor (G-CSF), and macrophage phases of the cell cycle however a fraction of tumor inflammatory protein (MIP-2) levels, as well as the cells in non-vulnerable cell cycle phases remain drug- neutrophil count, after MRSA infection of burn-injured resistant. Immunotherapy represents a promising mice (Kinoshita et al., 2011). approach to overcome the limitation of phase-specific Cytokine quantification may assist in understanding drugs and improve their clinical efficacy. The cytokines the mechanisms leading to repeated IVF/ICSI failure: associated with drug resistance, may represent potential either depletion of cytokines necessary for the apposition- serum biomarkers or novel drug targets. Mechanism adhesion, or an excess of cytokines leading to local of action of some anti cancer drugs by inducing or cytotoxicity, may impair the implantation of the embryo. inhibiting specific cytokines. alpha-Galactosylceramide Follicular concentration of G-CSF appears as a useful (alpha-GalCer) shows antitumor effects by activating biomarker of oocyte competence before fertilization natural killer (NK) cells indirectly through stimulation (Ledee et al., 2011). of the secretion of cytokines IL-18. The safety profile of IL-18 and its positive interactions with select anticancer Role of IL-18 Cytokines in Cancer Diagnosis chemotherapeutic agents strongly supports the clinical investigation of this combinatorial approach. IL-18 is a pro inflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, Role of IL-18 in chemo sensitive mediated by the induction of interferon (IFN)γ. Chronic Tumor immunotherapy with IL-18 can significantly inflammation is recognized as a predisposing factor for augment the killing fraction of phase-specific the development of cancer, but the molecular mechanisms chemotherapeutic drugs and provide survival benefit. linking inflammation and tumorigenesis have remained Drug-resistant cells were more immunogenic with elusive. Some cytokines IL-2, IL-11, transforming growth elevated expression of MHC-I and Fas (Alagkiozidis et al., factor (TGF) beta) stimulate, while others IL-12, IL-18, 2011). Serum IL-18 concentration predicted the clinical Interferons (IFNs) inhibit breast cancer proliferation and/ outcome of patients with aggressive non-Hodgkin’s or invasion. Thus suggesting careful preclinical studies lymphoma treated with cyclophosphamide, doxorubicin, are needed to determine the proper application of IL-18 vincristine, and prednisolone (CHOP). High serum levels in cancer therapy. increases overall survival rate in DLBCL. The high serum IL-18 is a diagnostic marker IL-18 patients with poor prognostic group in revised The IL-18 level in gastric cancer patient group was IPI or with non-germinal center B-cell phenotype had a significantly higher than that in gastric ulcer patient group. very poor prognosis. Serum IL-18 might be a powerful The IL-6 level in gastric cancer patients with distant prognostic factor for DLBCL. (Tsurumi et al., 2011). IL- metastasis was significantly higher than that in those 18 in combination with alpha-GalCer exerts an antitumor with no metastasis. The role of IL-10 and IL-12 levels effect on NK cell-sensitive tumors primarily by the in gastric cancer patients was to provide data with no direct stimulation of NK cells by IL-18 and the indirect significant difference. Serum IL-6 and IL-18, but not IL- stimulation of NK cells by alpha-GalCer through its 10 and IL-12 levels may be the useful biological markers activation of NKT cells (Nishio et al., 2008). Interleukin of clinical correlation and prognostic factor in patients (IL)-18 plays important roles in cancer progression with gastric cancer. Moreover, IL-18 could serve as a and metastasis. IL-18bp-Fc treatment was effective diagnostic marker for gastric cancer with a high positive in inhibiting the lung metastasis tumor progression, predictive value (Thong et al., 2006). VEGF levels in validated by ex vivo examination of the lung (Cao et al., induced sputum may have a prognostic role in the survival 2008). Selenium inhibits IL-18 gene expression in a dose- of small cell lung cancer (SCLC). The ratio VEGF/IL-18 dependent manner. IL-18 protein level was suppressed in induced sputum differs between non-small cell lung by treatment with selenium. The wound-healing assay cancer (NSCLC) and SCLC, indicating differences in revealed that the anti-metastatic effect of selenium was angiogenesis mechanisms and immunological response abrogated by treatment with exogenous IL-18. These in these two major histological types of lung cancer results suggest that selenium might be a potent inhibitor Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5358 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.11.5353 hepatic tissue to colon carcinoma metastasis. Gut. (Rovina et al., 2011). The role of alpha foetoprotein (AFP) Bouzgarrou N, Hassen E, Schvoerer E, et al (2008). Association in the diagnosis of advanced HCC is well recognized. of interleukin-18 polymorphisms and plasma level with the Increased levels of circulating interleukin-18 (IL-18) a outcome of chronic HCV infection. J Med Virol, 80, 607-14. suitable marker for the diagnosis of HCV-related HCC Cao Q, Cai W, Niu G, He L, Chen X (2008). Multimodality complementary to AFP, especially in cases with AFP level imaging of IL-18--binding protein-Fc therapy of experimental less than the diagnostic value (Mohran et al., 2011). IL-18 lung metastasis. Clin Cancer Res, 14, 6137-45. was an early and the most reliably detected host response Cao R, Farnebo J, Kurimoto M, Cao Y (1999). IL-18 acts as an to HCV infection measured in blood (Chattergoon et al., angiogenesis and tumor suppressor. FASEB J, 13, 2195-202. 2011). Inflammation regulated by is NOD-like receptor Carbone A, Vizio B, Novarino A, et al (2009). IL-18 paradox in pancreatic carcinoma: elevated serum levels of free IL-18 protein Nlrp3 through the assembly of proinflammatory are correlated with poor survival. J Immunother, 32, 920-31. protein complexes termed inflammasomes. IL-18 Chattergoon MA, Levine JS, Latanich R, et al (2011). High production downstream of the Nlrp3 inflammasome plasma interleukin-18 levels mark the acute phase of is critically involved in protection against colorectal hepatitis C virus infection. J Infect Dis, 204, 1730-40. tumorigenesis (Zaki et al., 2010). Expression levels of the Cho D, Song H, Kim YM, et al (2000). Endogenous interleukin-18 IL-18 in the primary breast cancer tissue in relation to the modulates immune escape of murine melanoma cells by unchanged breast tissue in same patients is significantly regulating the expression of Fas ligand and reactive oxygen higher in breast cancer tumour tissue as compared to its intermediates. 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Immunotherapeutic Approach for Better Management of Cancer - Role of IL-18

Asian Pacific Journal of Cancer PreventionNov 30, 2012

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10.7314/apjcp.2012.13.11.5353
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Abstract

Interleukin-18 (IL-18) is an immune-stimulatory cytokine with antitumor activity in preclinical models. It plays pivotal roles in linking inflammatory immune responses and tumor progression and is a useful candidate in gene therapy of lymphoma or lymphoid leukemia. A phase I study of recombinant human IL-18 (rhIL-18) in patients with advanced cancer concluded that rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. Some viruses can induce the secretion of IL-18 for immune evasion. The individual cytokine activity might be potentiated or inhibited by combinations of cytokines. Here we focus on combinational effects of cytokines with IL-18 in cancer progression. IL-18 is an important non- invasive marker suspected of contributing to metastasis. Serum IL-18 may a useful biological marker as independent prognostic factor of survival. In this review we cover roles of IL-18 in immune evasion, metastasis and angiogenesis, applications for chemotherapy and prognostic or diagnostic significance. Keywords: Interleukin-18 - cancer - angiogenesis - immunotherapy - predictive marker Asian Pacific J Cancer Prev, 13 (11), 5353-5361 (Michael et al., 2008). IL-18 is a useful candidate gene Immuno Therapeutics in gene therapy of lymphoma or lymphoid leukemia. Immunotherapy is defined as the “treatment of (Zhang et al., 2004). The combination of IL-18 and IL-2 disease by inducing, enhancing, or suppressing an is considered a viable strategy to induce an antitumor immune response”. Immunotherapies designed to elicit or response in vivo (Young et al., 2001). Plasma levels amplify an immune response are classified as activation and mRNA levels of IL-18 and its converting enzyme, immunotherapies. Cytokines are small cell-signaling caspase-1, were significantly elevated in Cutaneous T-cell protein molecules that are secreted by the immune system lymphoma (Kei-ichi et al., 2006). and used extensively in intercellular communication. IL-18 plays pivotal roles in linking inflammatory IL-18 viral infections immune responses and tumor progression. It is a pro- Epstein-Barr virus (EBV) latently infects and inflammatory cytokine converted to a biologically active immortalizes B lymphocytes and causes lympho molecule by IL-1beta converting enzyme (caspase-1). proliferative malignancies. EBV nuclear antigen EBNA2 IL-18 has various biological activities after its secretion induces expression of the 2 chains of the interleukin-18 as an 18 kDa mature form. A wide range of normal and receptor (IL-18R) in Burkitt lymphoma (BL) cell lines cancer cell types can produce and respond to IL-18 through and in non-transformed B cells. EBNA2 expression is a specific receptor (IL-18R) belonging to the toll-like associated with IL-18R expression in vivo in EBV-positive receptor family. The activity of IL-18 is regulated by IL- B-lymphomas from AIDS patients (Franck et al., 2005). 18-binding protein (IL-18bp), a secreted protein possessing IL-18 expression in response to a viral latency protein the ability to neutralize IL-18. It stimulates natural killer and suggest that IL-18 may play an important role as (NK) and T cells and enhances Th1 immune response. It is an endogenous inducer of IFN-g expression, thereby an immune-stimulatory cytokine with antitumor activity in contributing to tumor regression (Lei et al., 2001). IL-18 preclinical models. It increases the serum concentrations binding protein (IL-18BP) is a circulating protein that of IFN-g, granulocyte macrophage colony-stimulating binds IL-18 and neutralizes its activity. IL-18 production is factor and soluble Fas ligand (Robertson et al., 2006). increases in chronic HCV infection. IFN-a administration A phase I study of recombinant human IL-18 (rhIL-18) increased IL-18BP plasma levels 3.24 fold 24 h resulting in in patients with advanced cancer concluded that rhIL-18 a 67.4% reduction of free IL-18. These anti-inflammatory can be safely given in biologically active doses to patients properties might account together with its antiviral action with advanced cancer. The rhIL-18 increases expression for its clinical efficacy in chronic hepatitis C (Kaser et al., of activation antigens on lymphocytes and monocytes 2002). Institute of Genetics and Hospital for Genetic Diseases, Osmania University , Begumpet, Hyderabad, India *For correspondence: hemaprasadm@yahoo.com Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5353 Manohar Babu Kuppala et al a major anti-tumor activity via stimulation of a T-helper IL-18 Effects on Different Cancers type 1 (Th1) and T-helper type 2 (Th2) immune responses. IL-18 is a systemic, multifunctional cytokine with Intra-tumoral cytokine delivery has therapeutic potential both pro-cancerous and anti-cancer activities. There is for immunotherapy of cancers. growing evidence suggesting that IL-18 levels may affect Cytokine expression profiles may depend on type individual to virus-associated neoplasia and that single of cancer. The Th1 cytokines, particularly IL-12, were nucleotide polymorphisms within the gene may influence increased in adjacent mucosa of colorectal adenoma, its production. Variations in the DNA sequence in the IL- but all Th1 cytokines significantly decreased in adjacent 18 gene promoter may lead to altered IL-18 production, mucosa of colorectal carcinoma (Cui et al., 2007). IL-6 and so this can modulate an individual’s susceptibility. concentration increased as the tumor stage progressed, and IL-18 gene promoter polymorphism is reported to be a a significant difference appeared between stage of head genetic risk factor for several types of cancer (Han et al., and neck squamous cell carcinoma patients (Mojtahedi et 2003). al., 2011). IL-18, a cytokine that plays an important role in the IL-18 gene promoter polymorphism T-cell-helper response, acts as an angiogenic factor and Reporter gene assay reveals the significance of SNPs a tumor suppressor. There is a significant difference in of alleles in IL-18 gene promoter in HepG2 and Hep3B the levels of IL-18 between breast cancer patients with cells are associated with the presence of HCC (Kim et metastatic and non-metastatic cases. IL-18 is an important al., 2009). Significant genotype differences in the IL-18 non-invasive marker suspecting metastasis (Eissa et al., promoter region (-607) between the lung cancer patients 2005) Metastatic patients showed significantly higher and controls in Iranian population (Farjadfar et al., 2009). IL-18 mean values with respect to both healthy controls C allele at position -607 was associated with a higher risk and non-metastatic patients (Lissoni et al., 2000). of cirrhosis and HCC (Bouzgarrou et al., 2008). Co-administration of low-dose IL-2 plus IL-18 induced Significant difference in the frequency of -137 G/C a potent primary response to murine neuroblastoma genotype were found in colorectal cancers, nasopharyngeal and activation of natural killer cells in the tumor (Nong et al., 2009), breast cancer (Khalili et al., 2009), microenvironment. mIL-12 and mIL-18 synergistic cervical cancer (Sobti et al., 2008) and prostate cancers effect inhibit tumor angiogenesis (Coughlin et al., 1998). (Liu et al., 2007). Haplotype analysis showed statistical IL-2 plus IL-18cytokine treatment shows complete and significance in patients with stomach cancer -607 C/-137 durable antitumor response (Redlinger et al., 2003). C and -607 A/-137 G and in patients with colorectal cancer Intratumoral treatment with IL-18 and IL-12-encoding and esophageal squamous cell carcinoma (Wei et al., 2007; plasmid DNA has antitumor effects, which is well tolerated Haghshenas et al., 2009). and thus holds promise for the treatment of patients with metastatic melanoma (Muller et al., 2011). Both IL-10 and IL-18 levels in the peritoneal cavity increased with Effect of Combinational Cytokines with IL-18 tumor progression. Peritoneal exudates cells capable on Outcome of Cell Proliferation of producing IFN-gamma in response to IL-18 may be influenced by local IL-10 levels in the peritoneal cavity Different cytokines show dissimilar activities on (Majima et al., 2002). IFN-gamma, IL-15, and IL-18were cancer progression. Cytokines are key players exerting induced in patients treated with rhIL-12. The down- tumor and anti-tumor properties in the biological processes modulation of IFN-gamma induction during rhIL-12 of malignant tumors. The individual cytokine activity treatment did not relate to IL-10 production or alterations might potentiate or inhibited by combination of cytokines. in rhIL-12 bioavailability but was associated with an The relationship between pro-inflammatory and anti- acquired defect in lymphocyte IFN-gamma production inflammatory cytokines are responsible for the presence in response to IL-12, IL-2, or IL-15 (Gollob et al., 2000). and intensity of cancer progression. These cytokines have Table 1. IL-18 Promoter Polymorphism and Association with Cancer Progression in Different Cancers S.No -607 -137 Type of Cancer Patients Vs Association with Cancer out come Reference C/A G/C Control cancer progression 1 C C polycystic ovary syndrome 118 Vs 79 Not Associated Protective role Yang et al., 2010 2 A -- lung cancer 73 Vs 97 Associated cancer risk Farjadfar et al., 2009 3 A G GI cancers 232 Vs 312 Associated Protective role Haghshenas et al., 2009 4 A C Nasopharyngeal 250 Vs 270 Associated cancer risk Nong et al., 2009 5 A C ovarian cancer 85 Vs 158 Not Associated No role Samsami et al., 2009 6 A CC breast cancer 250 Vs 206 Associated Protective role Khalili et al., 2009 7 A C head and neck carcinoma 111 Vs 212 Not Associated No role Asefi et al., 2009 8 C C Cervical cancer 115 Vs 180 Associated Increased Cancer risk Sobti et al., 2008 100.0 9 A -- Nasopharyngeal carcinoma 163 Vs 164 Not Associated Increased cancer risk Farhat et al., 2008 6.3 12.8 10.1 20.3 10 A -- oral cancer 149 Vs 89 Not associated No role Vairaktaris et al., 2007 10.3 11 C -- Esophageal carcinoma 235 Vs 250 Associate Increased risk Wei et al., 2007 25.0 30.0 75.0 12 A C prostate cancer 265 Vs 280 Associate Increased risk Liu et al., 2007 75.0 46.8 56.3 51.1 Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 51.7 54.2 50.0 31.3 30.0 25.0 38.0 33.1 31.3 31.3 30.0 27.6 25.0 23.7 Newly diagnosed without treatment Newly diagnosed with treatment Persistence or recurrence Remission None Chemotherapy Radiotherapy Concurrent chemoradiation DOI:http://dx.doi.org/10.7314/APJCP.2012.13.11.5353 VEGF and IL-18 are markers for transformation of cancer progression and metastasis remains controversial. benign cells to metastatic cancer cells. Concentrations of The regulation of the IL-18 secretion process is an VEGF and IL-18 in the serum are sensitive tumor markers important step in tumor progression. in this patient group before and after treatment. High production of VEGF was associated with low production Il-18 enhances cancer progression of IL-18 (Jablonska et al., 2005). PEG interferon alpha- Chronic inflammation is associated with tumor 2b treatment was associated with decrease in plasma development and progression. IL-18 plays a central role basic fibroblast growth factor and increase in plasma in inflammation and the immune response, contributing interleukin-18. Bevacizumab therapy reduces tumor to the pathogenesis and pathophysiology of infectious and blood flow and resulting anticancer activity. No significant inflammatory diseases. High levels of IL-18 production changes in tumor blood flow were observed following may play a major role in the growth, invasion and PEG interferon (Yao et al., 2008). metastasis of renal cancer (Saenz et al., 2010). Higher Cytokines are responsible for progression of cancers. expression of IL-18 is detected in various cancer cells Serum IL-12 and IL-18 levels were higher in patients with (Park et al., 2007). Patients with high serum IL-18 levels IV stage of esophageal cancer (Diakowska et al., 2006). had a poorer survival than those with low serum IL-18 Intratumoral expressions of IL-12 and IL-18 can play an levels. Serum IL-18 level, but not IL-6 and IL-12 levels, important role in progression and metastasis of gastric was a significant and independent prognostic factor of cancer (Ye et al., 2007). Serum IL-12 and IL-18 levels survival in hepato cellular carcinoma (Tangkiivanich were significantly higher and increased in patients as the et al., 2007). Signaling through the adaptor protein pathologic stage progressed in patients with esophageal myeloid differentiation factor 88 (MyD88) promotes carcinoma. IL-12 and IL-18 levels correlate with a certain carcinogenesis in several cancer models (Salcedo et al., depth of invasion and might be useful tumor markers in 2010). patients with esophageal carcinoma (Tsuboi et al., 2004). Interleukin 18 binding protein (IL-18BP), a potent inhibitor of interleukin 18, significantly up regulated in large volume disease. Elevated IL-18BP secretion Role of IL-18 in Cancer Progression from cancer cells suggests an attempt by cancer to IL-18 is a pleiotropic, pro-inflammatory cytokine plays escape immune surveillance. IL-18BP merits further a critical role in tumor migration, invasion, and metastasis, study as a marker of aggressive prostate cancer and as with dual effects on tumor development and progression. a therapeutic target (Fujita et al., 2011). IL-18 inhibits Immunosuppressive cytokines subvert innate and cancer cell immune surveillance by indirect expression adaptive immune responses during cancer progression. of programmed death-1 gene. IL-18 produced by tumor IL-18 increases the escape immune recognition, increase cells promotes the development of NK-controlled adherence to the microvascular wall and induce production metastases in a PD-1-dependent manner. Accordingly, of angiogenic and tumor growth-stimulating factors via PD-1 is expressed by activated mature NK cells in IL-18-dependent mechanism. Thus, the role of IL-18 in lymphoid organs of tumor bearers and is up regulated by IL-18, as an immunosuppressive cytokine in cancer (Terme et al., 2011). VEGF-D enhanced cell migration Table 2. Effects of Cytokines is blocked by inhibiting IL-18. VEGF-D increased IL-18 S.No Combination Type of Cancer Reference expression and secretion, suggesting that IL-18 is a critical Anti Tumor Activity: mediator for VEGF-D-enhanced migration. VEGF-D 1 IL-12, IL-18 Mammary carcinoma Coughlin et al., 1998 induced a disintegrin and metalloprotease 33 (ADAM33) 2 IL-12, TNF-alpha Breast cancer Sabel et al., 2010 3 IFN-gamma, IL-12 Gastric carcinoma Majima et al., 2002 expression, which has a metalloproteinase domain (Kim 4 IL-10, IL-18 Gastric carcinoma Majima et al., 2002 et al., 2009). IL-18 is an important non-invasive marker 5 IL-2, IL-18 Neuroblastoma Redlinger et al., 2003 suspecting metastasis (Eissa et al., 2005). 6 IL-2, IL-12 Melanoma Muller et al., 2011 7 VEGF, IL-18 Oral cavity cancer Jablonska et al., 2005 Tumor Progression: Mechanism of IL-18 in cancer progression 1 IL-12, IL-18 Eesophageal carcinoma Diakowska et al., 2006 Hypoxia induces the transcription and secretion of IL- 2 IL-12, IL-18 Gastric cancer Sabel et al., 2010 18, which subsequently induces the expression of hypoxia- 3 IL-12, IL-18 Esophageal carcinoma Tsuboi et al., 2004 inducible factor-1alpha (HIF-1alpha). Mechanistically, 4 IL-10, IL-12 Head and neck squamous cell Jebreel et al., 2007 IL-18 induces HIF-1alpha through the activity of the *Anti Tumor Activity S. No (1-6)=Nature: Synergism and S. No GTPase Rac1, which inducibly associates with the IL- (7)=Nature: Antagonism. **Tumor Progression S. No (1-3)=Nature: Synergism and S. No (4)=Nature: Antagonism 18receptor beta (IL-18Rbeta) subunit, via a PI3K-AKT- Table 3. Role of IL-18 in Cancer Progression S. No Activity of IL-18 Angiogenic protein Type of Cancer Reference 1 Angiogenesis Down regulation of filamentous-actin polymerization and tensin Gastric cancer cell lines Kim et al., 2007 2 Angiogenesis alpha(v)beta(3) integrin Micro vascular endothelial cell (HMVEC) Park et al., 2001 3 Anti- angiogenesis Activation of T helper type 1 cells Colon carcinoma Tasaki et al., 2000 4 Tumor suppressor Inhibiting fibroblast growth factor-2 Carcinoma Cao et al., 1999 5 Inhibit immune surveillance expression of programmed death-1 Lymphoid carcinoma Terme et al., 2011 6 Inhibiting VEGF disintegrin and metallo protease 33 (ADAM33) Gastric cancer Kim et al., 2009 7 Metastasis Induction hypoxia-inducible factor-1alpha (HIF-1alpha) Carcinoma Kim et al., 2008 Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5355 Manohar Babu Kuppala et al NF-kappaB-dependent pathway. HIF-1alpha-mediated IL-18R-triggered signaling pathway increased activities of tumor progression, in which the induction of IL-18 by extracellular matrix metalloproteinase (MMP)-9, MMP-3, hypoxia or inflammatory cells augments the expression and MMP-2 by IL-18, which upregulated the mRNA levels of both HIF-1alpha and tumor cell metastasis (Kim et of MMP-3 and MMP-9 in a NF-κB-dependent manner al., 2008). (Zang et al., 2011). IL-18 grow/invade and evade immune surveillance in the hosts. Role of IL-18 in Immune Evasuion Mechanism of immune suppression by IL-18 A strong cell-mediated immune response is critical for Said et al. showed that inflammatory cytokines cause controlling viral infections and is regulated by a number an IL-10-dependent inhibition of CD4 T-cell expansion of cytokines. Large-scale genome studies have found and function by up-regulating PD-1 levels on monocytes correlations between single-nucleotide polymorphisms which leads to IL-10 production by monocytes after (SNPs) in the IL 18 promoter and spontaneous control of binding of PD-1 by PD-L. viral infections. IL-18 has been reported to inhibit hepatitis B virus replication in the liver of HBV transgenic mice. Role of IL-18 in Cancer Metastasis Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon Cancer cells metastasize to the other site after escaping (IFN)-γ by effector and memory CD8 T cells. Orthopox from the immune system and CD70, CD44 and vascular viruses, ectromelia virus, encode immune evasion endothelial growth factor (VEGF) play important roles molecules that specifically target IL-18 and IFN-gamma. in this process. Implantation and growth of metastatic Cancer cells metastasize to the other site after escaping cancer cells at distant organs is promoted by inflammation- from the immune system and vascular endothelial growth dependent mechanisms. factor (VEGF) play important roles in this process. IL-18 is a pro inflammatory cytokine, key marker CD8 T cells produce IFN-γ and upregulate CD25 for matastasis. IL-18 levels suppress CD70 expression following exposure to certain combinations of IL-12, and increases immune susceptibility of cancer cells. IL-18, and IL-21. The unresponsiveness of exhausted Endogenous IL-18 facilitate cancer cell immune escape CD8 T cells is associated with down regulation of the by suppressing CD70 and increasing metastatic ability IL-18-receptor-α (IL-18Rα). Exhausted T cells lose by upregulating CD44 and VEGF (Kang et al., 2009). their susceptibility to antigen-independent activation Expression of IL-18/IL-18R were remarkably up regulates by cytokines, which compromises their ability to detect and triggered signaling pathway related to metastasis in bacterial co-infections (Ingram et al., 2011). Absence hepatocellular carcinoma (Zang et al., 2011). Expression of both IL-12p40 and IL-18 resulted in increased of discoidin domain receptor 2 (DDR2) is essential for susceptibility to infection and reduction in NK and CTL metastatic activity as it is regulate expression of IL-18 in responses. IL-12p40 and IL-18 act in concert and play an hepatic stellate cells (HSC). DDR2 deficiency in HSCs important antiviral role through the up-regulation of IFN- led to decreased gene expression of interleukin IL-18 and gamma production and cell-mediated immune responses insulin-like growth factor-I; and increased gene expression (Wang et al., 2009). Post transplant lympho proliferative of prometastatic factors IL-10, transforming growth disease tissues express significantly lower levels of IL- factor (TGF)β and vascular endothelial growth factor 18 and interferon-gamma permitting the uncontrolled (VEGF) (Badiola et al., 2011). Erythroid differentiation expansion of Epstein-Barr virus (EBV)-infected B regulator (Erdr1) is a stress-related survival factor. The lymphocytes, compared to lymphoid tissues diagnosed expression of Erdr1 is negatively correlated with IL-18 with acute EBV-induced infectious mononucleosis expression. Erdr1 over expression markedly inhibited (Setsuda et al., 1999). the level of cell migration, invasion, and proliferation in IL-18, can enhance Fas ligand expression and suppress B16F10 cells in vitro (Jung et al., 2011). Selenium can the immune system (Cho et al., 2000). Cancer cells prevent metastasis by inhibiting IL-18 gene expression escape immune response by IL-18 and IL-18 receptors in a dose-dependent manner. Selenium might be a potent expression. IL-18 dose-dependently enhances proliferation inhibitor of the metastatic capacity of melanoma cells, via accompanied by nuclear factor kappaB activation. IL-18- down-modulation of IL-18 expression (Song et al., 2011). pretreated gastric cancer cells, decreased susceptibility to IL-1 gene is frequently expressed in metastases from perforin or interferon-gamma production (Majima et al., patients with several types of human cancers. IL-1Ra 2006). IL-18 plays a key role in regulating the immune escape by production of Thrombospondin (TSP-1). TSP-1 is known to inhibit angiogenesis in several cancers. IL-18 enhanced the expression of phosphorylated JNK. Overall, these results suggest that IL-18 plays a key role in TSP-1 expression involving JNK (Kim et al., 2006). Endogenous IL-18 facilitate cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF (Kang et al., 2009). IL-18 show dual effects on inhibition HBV replication and promotion of Figure 1. Mechanism of Immune Suppression by IL-18 metastasis and migration in human hepatocytes. IL-18/ Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5356 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.11.5353 inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers (Elaraj et al., 2006). Resveratrol is anti inflammatory drug remarkably inhibited hepatic retention and metastatic growth of melanoma cells. The mechanism involved IL-18 blockade by resveratrol prevented IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature and inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells (Salado et al., 2011). Furthermore, IL-   18-induced C6 migration and microfilament disassembly Figure 2. Mechanism of IL-18 in Angiogenesis by were antagonized by iNOS inhibitor, guanylate cyclase Different Pathways. IL-18; Interleukin-18, MCP-1; (GC) inhibitor and protein kinase G (PKG) inhibitor. monocyte chemoattractant protein 1, SDF-1alpha; stromal cell- derived factor 1alpha, PKCdelta; protein kinase Cdelta, PI3K; IL-18 secreted by microglia, enhanced migration of C6 phosphatidylinositol 3-kinase, ATF-2; activating transcription glioma through NO/cGMP pathway (Yen et al., 2011). factor 2 Serum IL-18 negatively associated with overall survival in small cell lung cancer (NSCLC). Serum IL-18 levels MAPK, and activating transcription factor 2 (ATF-2) in were significantly higher in NSCLC with metastasis than fibroblasts in a time-dependent manner, with JNK-2 being in NSCLC without metastasis (Okamoto et al., 2009). upstream of PKCdelta, ATF-2, and NFkappaB. IL-18 has a unique role in inducing the secretion of angiogenic Role of IL-18 in Angiogenesis SDF-1alpha/CXCL12, MCP-1/CCL2, and VEGF in RA ST fibroblasts, via distinct signaling intermediates (Amin Cell migration and angiogenesis are key steps in tumor et al., 2007). metastasis. The relationship between pro-angiogenic and anti-angiogenic factors is responsible for the presence and IL-18 enhances angiogenesis intensity of neoangiogenesis. IL-18, a cytokine belonging IL-18 is associated with the induction of angiogenic to the IL-1 family, and is potent cytokine that induces the factors, migration and malignant progression of tumors. neo vascularization. IL-18 also called interferon-gamma Inhibiting IL-18 markedly reduced the level of Vascular (IFN-gamma)-inducing factor, has been characterized endothelial growth factor (VEGF)-enhanced migration, as a potent IFN-gamma-inducing cytokine. IL-18 is a and IL-18 increases cell migration directly through highly regulated inflammatory cytokine that is elevated filamentous-actin polymerization and tensin down in synovial tissues and synovial fluids of patients with regulation (Kim et al., 2007). Human IL-18 induces micro rheumatoid arthritis (RA). IL-18 induces endothelial cell vascular endothelial cell (HMVEC) migration. IL-18 migration and angiogenesis by binding and activating appears to act on HMVECs via alpha(v)beta(3) integrin. endothelial cells and indirectly by vascular endothelial The angiogenesis is independent of the contribution of growth factor. IL-18 mediates all these inflammatory local TNF-alpha. Down-regulation of IL-18 activity or processes by binding to its receptor, IL-18 receptor, and AP-1 signal pathway can be potential therapeutic targets initiating the activation of different signaling cascades for rheumatoid arthritis. VEGF plays an important leading to changes in target cells gene expression and role in angiogenesis in rheumatoid synoviocytes (Cho behavior. IL-12 and IL-18 play an important role as et al., 2006). Microvascular abnormalities are one immunomodulatory factors in cancer pathogenesis (Volin of the most important causes of persistent diabetic et al., 2011). complications. Higher serum levels of sE-selectin and IL-18 were demonstrated in diabetic patients compared Mechanisms of IL-18 in angiogenesis to controls. Significant differences of sE-selectin and IL- IL-18 significantly enhanced the production of stromal 18 serum concentrations were observed between diabetic cell-derived factor 1alpha (SDF-1alpha)/CXCL12, patients with microangiopathy and controls suggest that monocyte chemoattractant protein 1 (MCP-1)/CCL2, and abnormalities in nailfold capillaroscopy may reflect the vascular endothelial growth factor (VEGF). IL-18-induced extent of microvascular involvement and are associated SDF-1alpha/CXCL12 up-regulation was dependent on with higher sE-selectin and IL-18 serum levels, as well JNK, p38 MAPK, phosphatidylinositol 3-kinase (PI3K), as with microangiopathic complications in diabetic and NFkappaB. IL-18-induced production of SDF-1alpha/ patients (Kuryliszyn et al., 2011). Hyper glycaemia CXCL12 was also dependent on protein kinase Cdelta increases inflammatory cytokine concentration in the (PKCdelta), production of MCP-1/CCL2 was dependent blood. Elevated levels of IL-18, in patients with Type 2 on PKCalpha, not PKCdelta. IL-18-induced MCP-1/CCL2 diabetes mellitus (DM2) and nephropathy. Recombinant production was mediated by JNK, PI3K, and NFkappaB. human IL-18 injected intra dermally to murine skin IL-18 induced phosphorylation of JNK, PKCdelta, p38 Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5357 Manohar Babu Kuppala et al induced significant neovascular reaction. DM2 patients of the metastatic capacity of melanoma cells, via down- sera contained higher concentration of IL-18 and induced modulation of IL-18 expression (Song et al., 2011). stronger neovascular reaction in mice skin than did the sera High levels of interleukin (IL)-12 and IL-18 were of corresponding control people (Skopinski et al., 2005). associated with a sustained virological response. IL-18 regulates pathogenic retinal neovascularization Conversely, high baseline IL-10 levels were significantly by promoting its regression rather than inhibiting its associated with a nonresponse to treatment. In multivariate development in an oxygen-induced retinopathy and is a analysis, low IL-10, high IL-12, and high IL-18 levels useful, new approach to treating retinopathy in humans were independently associated with an SVR. Serum IL- (Qiao et al., 2007). 10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin (Yoneda et al., 2011). Methicillin-resistant Staphylococcus IL-18 and Chemotherapy aureus (MRSA) infection is a grave concern in burn- Resistance to chemotherapy is the major cause of failure injured patients. IL-18 treatment increased the serum in cancer treatment. Time-dependent chemotherapeutic tumor necrosis factor (TNF), IL-17, IL-23, granulocyte agents can selectively target tumor cells in susceptible colony-stimulating factor (G-CSF), and macrophage phases of the cell cycle however a fraction of tumor inflammatory protein (MIP-2) levels, as well as the cells in non-vulnerable cell cycle phases remain drug- neutrophil count, after MRSA infection of burn-injured resistant. Immunotherapy represents a promising mice (Kinoshita et al., 2011). approach to overcome the limitation of phase-specific Cytokine quantification may assist in understanding drugs and improve their clinical efficacy. The cytokines the mechanisms leading to repeated IVF/ICSI failure: associated with drug resistance, may represent potential either depletion of cytokines necessary for the apposition- serum biomarkers or novel drug targets. Mechanism adhesion, or an excess of cytokines leading to local of action of some anti cancer drugs by inducing or cytotoxicity, may impair the implantation of the embryo. inhibiting specific cytokines. alpha-Galactosylceramide Follicular concentration of G-CSF appears as a useful (alpha-GalCer) shows antitumor effects by activating biomarker of oocyte competence before fertilization natural killer (NK) cells indirectly through stimulation (Ledee et al., 2011). of the secretion of cytokines IL-18. The safety profile of IL-18 and its positive interactions with select anticancer Role of IL-18 Cytokines in Cancer Diagnosis chemotherapeutic agents strongly supports the clinical investigation of this combinatorial approach. IL-18 is a pro inflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, Role of IL-18 in chemo sensitive mediated by the induction of interferon (IFN)γ. Chronic Tumor immunotherapy with IL-18 can significantly inflammation is recognized as a predisposing factor for augment the killing fraction of phase-specific the development of cancer, but the molecular mechanisms chemotherapeutic drugs and provide survival benefit. linking inflammation and tumorigenesis have remained Drug-resistant cells were more immunogenic with elusive. Some cytokines IL-2, IL-11, transforming growth elevated expression of MHC-I and Fas (Alagkiozidis et al., factor (TGF) beta) stimulate, while others IL-12, IL-18, 2011). Serum IL-18 concentration predicted the clinical Interferons (IFNs) inhibit breast cancer proliferation and/ outcome of patients with aggressive non-Hodgkin’s or invasion. Thus suggesting careful preclinical studies lymphoma treated with cyclophosphamide, doxorubicin, are needed to determine the proper application of IL-18 vincristine, and prednisolone (CHOP). High serum levels in cancer therapy. increases overall survival rate in DLBCL. The high serum IL-18 is a diagnostic marker IL-18 patients with poor prognostic group in revised The IL-18 level in gastric cancer patient group was IPI or with non-germinal center B-cell phenotype had a significantly higher than that in gastric ulcer patient group. very poor prognosis. Serum IL-18 might be a powerful The IL-6 level in gastric cancer patients with distant prognostic factor for DLBCL. (Tsurumi et al., 2011). IL- metastasis was significantly higher than that in those 18 in combination with alpha-GalCer exerts an antitumor with no metastasis. The role of IL-10 and IL-12 levels effect on NK cell-sensitive tumors primarily by the in gastric cancer patients was to provide data with no direct stimulation of NK cells by IL-18 and the indirect significant difference. Serum IL-6 and IL-18, but not IL- stimulation of NK cells by alpha-GalCer through its 10 and IL-12 levels may be the useful biological markers activation of NKT cells (Nishio et al., 2008). Interleukin of clinical correlation and prognostic factor in patients (IL)-18 plays important roles in cancer progression with gastric cancer. Moreover, IL-18 could serve as a and metastasis. IL-18bp-Fc treatment was effective diagnostic marker for gastric cancer with a high positive in inhibiting the lung metastasis tumor progression, predictive value (Thong et al., 2006). VEGF levels in validated by ex vivo examination of the lung (Cao et al., induced sputum may have a prognostic role in the survival 2008). Selenium inhibits IL-18 gene expression in a dose- of small cell lung cancer (SCLC). The ratio VEGF/IL-18 dependent manner. IL-18 protein level was suppressed in induced sputum differs between non-small cell lung by treatment with selenium. The wound-healing assay cancer (NSCLC) and SCLC, indicating differences in revealed that the anti-metastatic effect of selenium was angiogenesis mechanisms and immunological response abrogated by treatment with exogenous IL-18. These in these two major histological types of lung cancer results suggest that selenium might be a potent inhibitor Asian Pacific Journal of Cancer Prevention, Vol 13, 2012 5358 DOI:http://dx.doi.org/10.7314/APJCP.2012.13.11.5353 hepatic tissue to colon carcinoma metastasis. Gut. (Rovina et al., 2011). The role of alpha foetoprotein (AFP) Bouzgarrou N, Hassen E, Schvoerer E, et al (2008). Association in the diagnosis of advanced HCC is well recognized. of interleukin-18 polymorphisms and plasma level with the Increased levels of circulating interleukin-18 (IL-18) a outcome of chronic HCV infection. J Med Virol, 80, 607-14. suitable marker for the diagnosis of HCV-related HCC Cao Q, Cai W, Niu G, He L, Chen X (2008). Multimodality complementary to AFP, especially in cases with AFP level imaging of IL-18--binding protein-Fc therapy of experimental less than the diagnostic value (Mohran et al., 2011). IL-18 lung metastasis. Clin Cancer Res, 14, 6137-45. was an early and the most reliably detected host response Cao R, Farnebo J, Kurimoto M, Cao Y (1999). IL-18 acts as an to HCV infection measured in blood (Chattergoon et al., angiogenesis and tumor suppressor. FASEB J, 13, 2195-202. 2011). Inflammation regulated by is NOD-like receptor Carbone A, Vizio B, Novarino A, et al (2009). IL-18 paradox in pancreatic carcinoma: elevated serum levels of free IL-18 protein Nlrp3 through the assembly of proinflammatory are correlated with poor survival. J Immunother, 32, 920-31. protein complexes termed inflammasomes. IL-18 Chattergoon MA, Levine JS, Latanich R, et al (2011). High production downstream of the Nlrp3 inflammasome plasma interleukin-18 levels mark the acute phase of is critically involved in protection against colorectal hepatitis C virus infection. J Infect Dis, 204, 1730-40. tumorigenesis (Zaki et al., 2010). Expression levels of the Cho D, Song H, Kim YM, et al (2000). Endogenous interleukin-18 IL-18 in the primary breast cancer tissue in relation to the modulates immune escape of murine melanoma cells by unchanged breast tissue in same patients is significantly regulating the expression of Fas ligand and reactive oxygen higher in breast cancer tumour tissue as compared to its intermediates. Cancer Res, 60, 2703-9. expression in surrounding unchanged tissue of the same Cho ML, Jung YO, Moon YM, et al (2006). IL-18 induces the production of vascular endothelial growth factor (VEGF) in patients (Srabovic et al., 2011). IL-18 was reported as a rheumatoid arthritis synovial fibroblasts via AP-1-dependent potential biomarker of epithelial ovarian carcinoma (EOC) pathways. Immunol Lett, 103, 159-66. cells. IL-18 in EOC fluids is predominantly tumor-derived Coughlin CM, Salhany KE, Wysocka M, et al (1998). and that its lack of biological activity may represent Interleukin-12 and interleukin-18 synergistically induce a mechanism of tumor-escape (Orengo et al., 2010). murine tumor regression which involves inhibition of Effects of a new combination, cytosine deaminase (CD) angiogenesis. J Clin Invest, 101, 1441-52. + uracil phosphoribosyl transferase (UPRT)-mediated Cui G, Yuan A, Goll R, et al (2007). Distinct changes of dendritic gene-directed enzyme prodrug therapy (GDEPT) with cell number and IL-12 mRNA level in adjacent mucosa 100.0 interleukin (IL)-12 and IL-18, was effective against local throughout the colorectal adenoma-carcinoma sequence. Cancer Immunol Immunother, 56, 1993-2001. and systemic prostate cancer and improved survival. 6.3 12.8 10.1 20.3 Diakowska D, Markocka-Maczka K, Grabowski K, Lewandowski 10.3 Monitoring serum levels of IL-4 and MCP-1 may A (2006). Serum interleukin-12 and interleukin-18 levels in accurately reflect tumor burden and, hence, host response 25.0 30.0 75.0 patients with oesophageal squamous cell carcinoma. Exp to therapy (Khatri et al., 2009). Oncol, 28, 319-22. IL-18 show antitumor activity by promoting expansion 75.0 46.8 Eissa SA, 56.3 Zaki SA, El-Maghraby SM, Kadry DY (2005). 51.1 of gammadelta T cells. Incubation of gamma delta T cells 51.7 Importance of serum IL-18 and RANTES as markers for 54.2 50.0 in the presence with IL-18 produces higher levels GM- 31.3 breast carcinoma progression. J Egypt Natl Canc Inst, 17, 30.0 CSF, IFN-gamma, and TNF-alpha in human peripheral 51-5. blood mononuclear cells (PBMCs) (Li et al., 2010). Elaraj DM, Weinreich DM, Varghese S, et al (2006). The role of interleukin 1 in growth and metastasis of human cancer 25.0 xenografts. Clin Cancer Res, 12, 1088-96. 38.0 Acknowledgements 33.1 31.3 31.3 30.0 27.6 Elias AS, et al. 2009, PD-1 Induced IL10 Production by 25.0 23.7 Monocytes Impairs T-cell Activation in a Reversible Fashion. Dr. Devarajan Karunagaran, Dept. of Cancer Biology, Nature Medicine, 452-9. IIT Madras for support and guidance and Indian Academy Farhat K, Hassen E, Bouzgarrou N, et al (2008). 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Published: Nov 30, 2012

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