Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy

Natural killer (NK) cells, a crucial component of the innate immune system, have long been of clinical interest for their antitumor properties. Almost every aspect of NK cell immunity is regulated by interleukin-15 (IL-15), a cytokine in the common γ-chain family. Several current clinical trials are using IL-15 or its analogs to treat various cancers. Moreover, NK cells are being genetically modified to produce membrane-bound or secretory IL-15. Here, we discuss the key role of IL-15 signaling in NK cell immunity and provide an up-to-date overview of IL-15 in NK cell therapy. IL-15 and its combination with other reagent(s) are of interest in the field of cancer immunotherapy, yet its potential untoward side effects have at times required special management. A better understanding of IL-15 signaling can improve its utilization for antitumor activity and ideally allow for successful NK cell-based immunotherapy. IL-15 is a pleiotropic cytokine that promotes the survival, proliferation, and cytotoxicity of both NK and CD8+ T cells. As these cells take the lead in tumor destruction, the IL-15 pathway provides an exciting opportunity to enhance cancer cellular immunotherapy.Like IL-2, IL-15 signals through a receptor complex composed of IL-2/IL-15 receptor beta (β) chain and the common gamma chain (γc). Unlike IL-2, however, IL-15 does not support activation-induced T cell death or enhance the proliferation, function, or differentiation of CD4+ regulatory T cells.Administration of soluble (s) recombinant IL-15 and several IL-15 agonists has shown promising antitumor effects in preclinical murine models. These agents are currently under clinical investigation for treating hematological and solid tumor malignancies. sIL-15 and membrane-bound (m) IL-15 have also been genetically engineered into NK cells to enhance their survival, persistence, and activation in vivo.Obtaining mechanistic insights into how IL-15 regulates NK cell immune responses and generating novel IL-15 agonists can help improve NK cell-based immunotherapy.