Activation of the Interleukin-18 Signaling Pathway via Direct Receptor Dimerization in the Absence of Interleukin-18.

Interleukin 18 (IL-18) is a key cytokine involved in the activation of T and NK cells, which are major effector cells in tumor killing. However, recombinant IL-18 showed limited efficacy in clinical trials. A recent study showed the lack of efficacy was largely due to the existence of IL-18BP, a soluble decoy receptor for IL-18. It was shown that engineered IL-18 variants that maintained pathway activation, but avoided IL-18BP binding, could exert potent antitumor effects. In this study, we demonstrated an alternative strategy to activate IL-18 signaling through direct receptor dimerization. These results provide evidences that the IL-18 pathway can be activated by directly bridging the receptors and, therefore, bypassing the IL-18BP-mediated inhibition.