Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 97, Issue 4, Pages 665-675Publisher
OXFORD UNIV PRESS
DOI: 10.1189/jlb.5RU0714-360RR
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Funding
- Fondazione Compagnia di San Paolo
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG13518]
- FIRC, Fondazione Italiana per la Ricerca sul Cancro
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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-gamma-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-gamma 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 antitumor 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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