The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

Carbotti, Grazia; Barisione, Gaia; Orengo, Anna Maria; Brizzolara, Antonella; Airoldi, Irma; Bagnoli, Marina; Pinciroli, Patrizia; Mezzanzanica, Delia; Centurioni, Maria Grazia; Fabbi, Marina; Ferrini, Silvano

doi:10.1158/1078-0432.ccr-13-0568

Cited by 42 publications

(41 citation statements)

References 47 publications

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“…We initially chose the SKOV3 ovarian cancer cell line, which has been widely utilized as a serous ovarian adenocarcinoma cell model, and responds to IL-27 stimulation by up-regulating the expression of immune regulatory IL-18BP, IDO, and PD-L1 molecules [22, 23]. Since also IFN-γ up-regulates these molecules, we compared IL-27 and IFN-γ effects on the proteome.…”

Section: Resultsmentioning

confidence: 99%

“…However, our recent data showed that, beyond these anti-tumor effects, IL-27 also induces the expression of immune regulatory molecules such as IL-18BP, the natural inhibitor of the Th1-inducing cytokine IL-18, in ovarian cancer cells [22]. Perhaps more importantly, it induced the expression of the immune-suppressive molecules IDO and PD-L1, in human cancer cells, through the activation of STAT1 or STAT3 pathways, respectively [23].…”

Section: Introductionmentioning

confidence: 99%

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Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

et al. 2016

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IL-27, a member of the IL-12-family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-γ, induces the expression of IL-18BP, IDO and PD-L1 immune regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN-γ display a broad overlap of functions on human ovarian cancer cells. Indeed, among 990 proteins modulated by either cytokine treatment in SKOV3 cells, 814 showed a concordant modulation by both cytokines, while a smaller number (176) were differentially modulated. The most up-regulated proteins were common to both IFN-γ and IL-27. In addition, functional analysis of IL-27-regulated protein networks highlighted pathways of interferon signaling and regulation, antigen presentation, protection from natural killer cell-mediated cytotoxicity, regulation of protein polyubiquitination and proteasome, aminoacid catabolism and regulation of viral protein levels.Importantly, we found that IL-27 induced HLA class I molecule expression in human cancer cells of different histotypes, including tumor cells showing very low expression. IL-27 failed only in a cancer cell line bearing a homozygous deletion in the B2M gene. Altogether, these data point out to a broad set of activities shared by IL-27 and IFN-γ, which are dependent on the common activation of the STAT1 pathway. These data add further explanation to the anti-tumor activity of IL-27 and also to its dual role in immune regulation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

et al. 2016

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“…In prostatic cancer, urinary and serum IL-18BP levels are increased, and serum IL-18BP levels correlate with the Gleason score. A potential role of IL-27 in vivo is suggested by the expression of the 2 IL-27 chains (IL-27A and EBV-induced 3) in ovarian cancer-associated leukocytes [74]. Furthermore, in ovarian cancer, IL-18BP is increased in sera and even more in the ascites.…”

Section: Anti-cancer Effects Of Il-18mentioning

confidence: 99%

Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP

Fabbi

Carbotti

Ferrini

2014

Journal of Leukocyte Biology

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IL-18 is a proinflammatory and immune regulatory cytokine, member of the IL-1 family. IL-18 was initially identified as an IFN-γ-inducing factor in T and NK cells, involved in Th1 responses. IL-18 is produced as an inactive precursor (pro-IL-18) that is enzymatically processed into a mature form by Casp1. Different cells, such as macrophages, DCs, microglial cells, synovial fibroblasts, and epithelial cells, express pro-IL-18, and the production of bioactive IL-18 is mainly regulated at the processing level. PAMP or DAMP molecules activate inflammasomes, which trigger Casp1 activation and IL-18 conversion. The natural inhibitor IL-18BP , whose production is enhanced by IFN-γ and IL-27, further regulates IL-18 activity in the extracellular environment. Inflammasomes and IL-18 represent double-edged swords in cancer, as their activation may promote tumor development and progression or oppositely, enhance anti-tumor immunity and limit tumor growth. IL-18 has shown anti-tumor activity in different preclinical models of cancer immunotherapy through the activation of NK and/or T cell responses and has been tested in clinical studies in cancer patients. However, the dual role of IL-18 in different experimental tumor models and human cancers raises critical issues on its therapeutic use in cancer. This review will summarize the biology of the IL-18/IL-18R/IL-18BP system and will address the role of IL-18 and its inhibitor, IL-18BP, in cancer biology and immunotherapy.

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“…The induction of surface HLA class I expression by IL-27 and IFN-γ is related to the activation of the STAT1 signaling pathway, which is an essential mediator of both IFNs and IL-27 biological effects [19, 23, 26, 27]. Indeed, recent studies by proteomics [18] or gene expression profiling [29] in different cell types showed a broad overlap between IFN-γ and IL-27 effects, including the induction of several components of the HLA class I antigen presentation machinery.…”

Section: Discussionmentioning

confidence: 99%

“…In view of its immune-enhancing activities and direct anti-tumor effects IL-27 has been considered as a potential anti-tumor agent [25]. On the other hand, IL-27 induces the expression of immune-regulatory molecules such as the IL-18 natural inhibitor, IL-18BP [26], the tryptophan catabolic enzyme IDO and PD-L1 [27], in neoplastic cells. Therefore, IL-27 may have a dual role in anti-tumor immunity [28] and shares several immune-regulatory functions with IFN-γ, in relationship to the common usage of the STAT1 intracellular signaling pathway [18, 19, 23, 29].…”

Section: Introductionmentioning

confidence: 99%

IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells

Carbotti

Nikpoor

Vacca

et al. 2017

J Exp Clin Cancer Res

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BackgroundRecently, immunotherapy with anti-PD-1 antibodies has shown clinical benefit in recurrent Small Cell Lung Cancer (SCLC). Since anti-PD-1 re-activates anti-tumor Cytotoxic T Lymphocyte (CTL) responses, it is crucial to understand the mechanisms regulating HLA class I, and PD-L1 expression in HLA-negative SCLC. Here we addressed the role of IL-27, a cytokine related to both IL-6 and IL-12 families.MethodsThe human SCLC cell lines NCI-N592, -H69, -H146, -H446 and -H82 were treated in vitro with different cytokines (IL-27, IFN-γ, IL-6 or a soluble IL-6R/IL-6 chimera [sIL-6R/IL-6]) at different time points and analyzed for tyrosine-phosphorylated STAT proteins by Western blot, for surface molecule expression by immunofluorescence and FACS analyses or for specific mRNA expression by QRT-PCR. Relative quantification of mRNAs was calculated by the ΔΔCT method. The Student’s T test was used for the statistical analysis of experimental replicates.ResultsIL-27 triggered STAT1/3 phosphorylation and up-regulated the expression of surface HLA class I antigen and of TAP1 and TAP2 mRNA in four out of five SCLC cell lines tested. The IL-27-resistant NCI-H146 cells showed up-regulation of HLA class I by IFN-γ. IFN-γ also induced expression of PD-L1 in SCLC cells, while IL-27 was less potent in this respect. IL-27 failed to activate STAT1/3 phosphorylation in NCI-H146 cells, which display a low expression of the IL-27RA and GP130 receptor chains. As GP130 is shared in IL-27R and IL-6R complexes, we assessed its functionality in response to sIL-6R/IL-6. sIL-6R/IL-6 failed to trigger STAT1/3 signaling in NCI-H146 cells, suggesting low GP130 expression or uncoupling from signal transduction. Although both sIL-6R/IL-6 and IL-27 triggered STAT1/3 phosphorylation, sIL-6R/IL-6 failed to up-regulate HLA class I expression, in relationship to the weak activation of STAT1. Finally sIL-6R/IL-6 limited IL-27-effects, particularly in NCI-H69 cells, in a SOCS3-independent manner, but did not modify IFN-γ induced HLA class I up-regulation.ConclusionsIn conclusion, IL-27 is a potentially interesting cytokine for restoring HLA class I expression for SCLC combined immunotherapy purposes. However, the concomitant activation of the IL-6 pathway may limit the IL-27 effect on HLA class I induction but did not significantly alter the responsiveness to IFN-γ.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0608-z) contains supplementary material, which is available to authorized users.

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The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment

Cited by 42 publications

References 47 publications

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP

IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient Small Cell Lung Cancer cells

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