1. Academic Validation
  2. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP

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

  • J Leukoc Biol. 2015 Apr;97(4):665-75. doi: 10.1189/jlb.5RU0714-360RR.
Marina Fabbi 1 Grazia Carbotti 2 Silvano Ferrini 1
Affiliations

Affiliations

  • 1 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.
  • 2 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.
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.

Keywords

Th1 response; cancer immunotherapy; immune regulation.

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