Interleukin-15 biology and its therapeutic implications in cancer

Abstract

Cancer immunotherapy is designed to stimulate the immune system to reject and destroy tumors. Recently, interleukin-15 (IL-15), a member of the four α-helix bundle family of cytokines, has emerged as a candidate immunomodulator for the treatment of cancer. IL-15 acts through its specific receptor, IL-15Rα, which is expressed on antigen-presenting dendritic cells, monocytes and macrophages. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. It also enhances the cytolytic activity of CD8(+) T cells and induces long-lasting antigen-experienced CD8(+)CD44(hi) memory T cells. IL-15 stimulates differentiation and immunoglobulin synthesis by B cells and induces maturation of dendritic cells. It does not stimulate immunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15 activity could enhance innate and specific immunity and fight tumors. Here we review aspects of IL-15 biology that make it a promising agent for anticancer therapy. We also discuss preclinical models in which IL-15 has demonstrated antitumor activity and highlight ongoing clinical trials of IL-15 in patients with cancer and HIV infection.

Figure 1. Interleukin-15 genomic organization and gene expression

IL-15 is encoded by a 34 kb region on human chromosome 4q31. The IL-15 gene is made up of nine (1–8 and 4A) exons and eight introns of which 4 exons (5 through 8) code for the mature protein. There are 2 isoforms of IL-15 mRNA that differ in the length of their signal peptides. The originally identified form consisted of a 316 bp 5’-untranslated region (UTR), a 486 bp coding sequence, and a 400 bp 3’UTR that is translated into an IL-15 precursor protein with a long signal peptide (IL-15LSP) of 48 amino acids. The long signal peptide is encoded within exons 3–5. The other isoform has a short signal peptide of 21 amino acids (IL-15SSP) encoded by exons 4A and 5. Both isoforms produce the same mature protein; however, the two differ in that they have distinct intracellular trafficking. IL-15LSP is targeted to the Golgi apparatus, early endosomes and the endoplasmic reticulum secretory pathway where it is complex with IL15Rα. IL-15SSP is not secreted and appears to be restricted to the cytoplasm and nucleus.

Figure 2. Interaction of interleukin-2 (IL-2) with its receptor (IL-2R) contrasted to that of IL-15 and its receptor (IL-15R)

The high affinity IL-2R is a heterotrimeric complex composed of the common cytokine receptor gamma subunit (γc), a beta subunit (IL-2R/IL-15Rβ) that is also shared with the IL-15 receptor (IL-15R), and a private alpha subunit (IL-2Rα). All three subunits are expressed on activated NK, T and other immune cells. Receptor specificity is conferred by the alpha subunit of each cytokine (IL-2Rα or IL-15Rα) and signal transduction is mediated through IL-2R/IL-15Rβ and yc. For IL-2, all three subunits (IL-2Rα, IL-2R/IL-15Rβ, and γc) are expressed by the same cell and as a complex directly bind soluble IL-2. In contrast, the interaction of IL-15 with its receptor is more complex. Little IL-15 appears to be expressed in a free soluble state. Rather, IL-15 is presented in trans pre-associated with IL-15Rα by antigen-presenting cells to the IL-2R/IL-15Rβ and γc receptor subunits expressed on NK and T cells. IL-15 is expressed by monocytes/macrophages and dendritic cells and is stabilized by being associated with IL-15Rα in the endosomal-Golgi apparatus. The IL-15/IL-15Rα complex is secreted and expressed on the surface of monocytes and dendritic cells to present IL-15 to the IL-2R/IL-15Rβ and γc subunits expressed on NK and CD8+ T cells.