Targeting of IL-4 and IL-13 receptors for cancer therapy

The Th2 cytokines, interleukin (IL)-4 and -13, are structurally and functionally related. They regulate immune responses and the immune microenvironment, not only under normal physiological conditions, but also in cancer. Both cytokines bind to their high-affinity receptors and form various configurations of receptor subtypes. We and others have reported that IL-4 and IL-13 bind to IL-4Rα and IL-13Rα1 chains, forming functional receptors in cancer cells. IL-13 also binds with high affinity to a private chain IL-13Rα2. After forming ligand-receptor complexes, both cytokines initiate signal transduction and mediate biological effects, such as tumor proliferation, cell survival, cell adhesion and metastasis. In certain cancers, the presence of these cytokine receptors may serve as biomarkers of cancer aggressiveness. In a series of studies, we reported that overexpression of IL-4 and IL-13 receptors on cancer cells provides targets for therapeutic agents for cancer therapy. In addition, both of these cytokines and their receptors have been shown to play important roles in modulating the immune system for tumor growth. IL-4, IL-13 and their receptors seem to play a role in cancer stem cells and provide unique targets to eradicate these cells. In this review article, we summarize some of the important attributes of IL-4 and IL-13 receptors in cancer biology and discuss pre-clinical and clinical studies pertaining to recombinant immunotoxins designed to target these receptors.