Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy

SIMPLE SUMMARY: Emerging knowledge of the two type I cytokine family members IL-2 and IL-15 has led to critical therapeutic implications for cancer treatment. Here we discuss the distinct roles of IL-2 and IL-15 in activating various functions of T and NK cells with a particular focus on the signals that contribute to the resistance of immune suppressive factors within the tumor microenvironment. We furthermore highlight efforts to modify these cytokines to amplify their antitumor efficacy while minimizing toxicity. Finally, we summarize the clinical applications of IL-2 and IL-15 in metastatic cancer. ABSTRACT: The type I cytokine family members interleukin-2 (IL-2) and IL-15 play important roles in the homeostasis of innate and adaptive immunity. Although IL-2 and IL-15 receptor complexes activate similar signal transduction cascades, triggering of these receptors results in different functional activities in lymphocytes. While IL-2 expands regulatory T cells and CD4+ helper T cells, IL-15 supports the development of central memory T cells and NK cells. Recent data have provided evidence that IL-2 and IL-15 differ in their ability to activate T and NK cells to resist various forms of immune suppression. The diverse roles of these two cytokines have on immune cells lead to critical therapeutic implications for cancer treatment. In this review, we discuss the distinct roles of IL-2 and IL-15 in activating various functions in T and NK cells with a particular focus on the signals that participate in the resistance of tumor-derived immune suppressive factors. Furthermore, we summarize current clinical applications of IL-2 and IL-15 in metastatic malignancies, either as monotherapy or in combination with other agents, and highlight the future trends for research on these cytokine-based immunotherapies.