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

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.

Keywords: cytokine; immunotherapy; interleukin-15; interleukin-2.

Figure 1

Interaction of interleukin-2 (IL-2) and IL-15 with their receptors and downstream signaling pathways. Receptors for IL-2 and IL-15 share two mutual submits, the common cytokine receptor γ-chain (γc) and the β-chain IL-2/15Rβ. Secreted IL-2 binds to its unique receptor submit IL-2Rα while membrane-associated IL-15 is trans-presented by monocytes or dendritic cells to NK cells or CD8+ T cells through binding with IL-15Rα, and then forms the high-affinity heterotrimeric receptor complex allowing the activation of downstream signaling. Both IL-2 and IL-15 mainly trigger the phosphorylation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, which could be limited by CIS/SOCS as a negative feedback. The phosphorylated STAT dimers or tetramers then translocate into the nucleus to regulate the transcription of target genes. Other pathways including RAS/Raf/MAPK and phosphoinositol 3-kinase (PI3K)/AKT are also activated by the ligation of these cytokines, contributing to the complex physical impacts of IL-2 and IL-15 on various immune cells.