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

IL-18 is a proinflammatory and immune regulatory cytokine, member of the IL-1 family. IL-18 was initially identified as an IFN-g-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 pro-cessed into a mature form by Casp1. Different cells, such as macrophages, DCs, microglial cells, synovial fibro-blasts, 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 pro-duction is enhanced by IFN-g and IL-27, further regulates IL-18 activity in the extracellular environment. Inflamma-somes and IL-18 represent double-edged swords in cancer, as their activation may promote tumor develop-ment 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 tumormodels and human cancers raises critical issues on its therapeutic use in cancer. This review will summarize the biology of the IL-18/IL