The role of interleukin 15 in neoplasia.

Abstract

Interleukin 15 is a pleiotropic cytokine of the four α helix bundle family. Binding to a heterotrimeric receptor complex, which consists of a unique, high affinity IL‑15Rα‑chain and IL-2/IL-15Rβ and IL‑2Rγ chains, IL‑15 activates signaling pathways leading to activation and proliferation of T and B cells, as well as natural killer cells. At the same time, IL‑15 protects effector cells from T regulatory cells and does not induce immune tolerance. The significant regulatory action of IL‑15 on the immune system provides new opportunities for development of anti‑cancer therapies. As documented in many experiments using different tumor models, IL‑15 enhances antitumor effects. To improve the efficiency of IL‑15, several strategies, including combination with other anti‑cancer therapies such as chemotherapy, additional use of antibodies (anti‑PD‑L1, anti‑CTLA‑4, anti‑CD40), or other cytokines, have been evaluated. Increased anti‑tumor activity can also be obtained by using IL‑15 agonists. However, acting as a growth factor for immune cells but also for tumor cells, IL‑15 may promote their proliferation, survival and dissemination. Of significance seems the role of IL‑15 in the pathogenesis of hematological malignancies, which is due to the involvement in the proliferation and differentiation of NK, T and B cells. Currently, several experimental strategies are available to block biological activity of IL‑15. Among compounds inhibiting the activity of IL‑15 are not only monoclonal antibodies interacting directly with the cytokine or with IL‑15R subunits, but also mutant forms of IL‑15 and protein constructs.