IL-15 and IL-15Rα: Something old, something new, and something blue

NK cell-based immunotherapies have gained traction in the clinic for the treatment of cancer due to the ability of NK cells to directly lyse tumor cells. NK cells are being exploited in clinical trials using autologous and allogeneic NK cell infusion strategies alone or with hematopoietic stem cell transplantation. These strategies have rapidly evolved to exploit the therapeutic effects of NK cells transduced with chimeric antigen receptors and the utilization of IL-15 to induce NK cell persistence and expansion that seems to dominate current clinical trials. IL-15 is a member of the common receptor gamma chain (γc) family, which also includes IL-2, IL-4, IL-7, IL-9, and IL-21. This group of cytokines has a broad pleiotropic activity on both the innate and adaptive immune systems, with important therapeutic ramifications. The protein form of IL-15 contains two N-linked glycosylation sites at the C-terminus of the IL-15 protein, at N79 and N112, and disulfide bonds at positions C42-C88 and C35-C85, the former being homologous to the CC within IL-2. The IL-15 heterotrimeric receptor complex consists of a private IL-15 specific alpha subunit IL-15Rα (CD215), the IL-2/IL-15 receptor β (CD122), and the common γc receptor subunit (CD132) which are shared by the IL-2 receptor. The ability of IL-15 to stimulate NK cell responses, and its well-documented antitumor activity in preclinical models, support the development of clinical studies of IL-15 in cancer. IL-15 showed acceptable toxicity profiles in mouse and primate models and, thus, is increasingly recognized as a promising cytokine for the treatment of hematological and solid malignancies. IL-15 is currently being tested clinically in a number of formulations to enhance immunotherapy for several indications. Clinical studies of IL-15 or IL-15 superagonists, consisting of IL-15 linked to IL-15Rα portions, have been initiated; studies combining IL-15 with adoptive transfer of NK cells are ongoing in cancer patients. This review traces how our understanding of the complex regulation of IL-15 has evolved in time and how accumulated knowledge from the bench was translated in the clinic.