title: Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP.
abstract: 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.
authors.affiliation: Laboratory of Biotherapy, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy silvanodomenico.ferrini@hsanmartino.it marina.fabbi@hsanmartino.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.affiliation: Laboratory of Biotherapy, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Carbotti
authors.affiliation: Laboratory of Biotherapy, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy silvanodomenico.ferrini@hsanmartino.it marina.fabbi@hsanmartino.it.
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000502:physiology; D017321:Clinical Trials, Phase I as Topic; D003043:Cocarcinogenesis; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D058847:Inflammasomes / Q000502:physiology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology* / Q000627:therapeutic use; D020382:Interleukin-18 / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010586:Phagocytes / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011498:Protein Precursors / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D053724:Receptors, Interleukin-18 / Q000502:physiology; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism
chemical_list: C000589760:IL18 protein, human; D058847:Inflammasomes; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D011498:Protein Precursors; D053724:Receptors, Interleukin-18; C118370:interleukin-18 binding protein; D020170:Caspase 1
keywords: Th1 response; cancer immunotherapy; immune regulation