Interleukin 15 as a promising candidate for tumor immunotherapy

https://doi.org/10.1016/j.cytogfr.2011.04.001Get rights and content

Abstract

Interleukin 15 participates in the development of important immune antitumor mechanisms. It activates CD8+ T cells, natural killer (NK) cells, NK T cells, and can promote the formation of antitumor antibodies. IL-15 can also protect T effector cells from the action of T regulatory cells and reverse tolerance to tumor-associated antigens. In pre-clinical studies IL-15 has been found to demonstrate potentiated antitumor effects following pre-association with IL-15Rα, or when used in combination with chemotherapy, adoptive therapy, monoclonal antibodies, and tumor vaccines. Although a clinical trial based on application of IL-15 in tumor patients has already begun, it is important to be aware of its potential side effects, including induction of autoimmunity and promotion of proliferation, survival, and dissemination of some tumor cells.

Introduction

Interleukin 15 (IL-15) was discovered as another T cell growth factor [1] and belongs to the family of the common gamma chain (γc) or four-helix-bundle cytokines, which includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. IL-15 displays pleiotropic functions in homeostasis and activation of both innate and adaptive immunity. Receptors for these cytokines share the common γc chain and have unique α chains. IL-2R and IL-15R have additional identical IL-2/15Rβ chains (reviewed in [2]); the similar structure of their receptors explains partial functional redundancy among γc chain cytokines. These cytokines nonetheless display unique features even if IL-2 is compared with IL-15, which shares two out of three chains in their receptors. Until recently, IL-2 has attracted the attention of oncologists as the only interleukin approved for tumor immunotherapy in the treatment of metastatic melanoma and renal cell carcinoma since 1992 [3]. However, the early enthusiasm associated with the use of IL-2 in tumor therapy has diminished, as durable complete responses were achieved in only a small percentage of patients given high-dose IL-2 therapy [4]. Application of high doses of IL-2 is also accompanied by severe toxicity [5], [6]. Furthermore, although IL-2 stimulates proliferation and differentiation of effector T cells, memory CD8+ T cells and natural killer (NK) cells (reviewed in [7]), strengthening the antitumor immune response, it may also limit the effectiveness of antitumor immunity because of its critical role in the differentiation and maintenance of regulatory T (Treg) cells [8] and the induction of activation-induced cell death of effector T lymphocytes [9]. As oncologists’ interest in IL-2 has waned, IL-15, another member of the γc chain family of cytokines, has proven significant as a cytokine with strong antitumor activity. Advantages of IL-15 in tumor immunotherapy result from its unique ability to activate important mechanisms of antitumor immunity, including development and activity of both NK cells [10], [11], [12] and CD8+ T cells [13], [14], [15], [16], and promoting a persistent immune response through its action on memory T cells [16], [17], [18], [19], [20]. What is more, IL-15 is less toxic [21] and less effective in inducing Treg cell activity, as compared with IL-2 [22], and in certain circumstances it can even protect human effector T cells from the action of Treg cells [23] (see below). IL-15 is at the top of the National Cancer Institute's list of agents with the greatest potential use in tumor immunotherapy [24], and the first clinical study of recombinant human IL-15 in adults with refractory metastatic melanoma and metastatic renal cell cancer is currently recruiting patients (http://clinicaltrials.gov/ct2/show/NCT01021059). Although the diverse functions of IL-15 facilitate the development of both innate and durable adaptive immunity, making it an ideal agent to be used either alone or in combination with other treatment modalities in tumor therapy, it is important to examine the peculiarities of its activity and be aware of the potential drawbacks and side effects of its application.

Section snippets

Expression of IL-15

The human IL-15 gene was mapped to chromosome 4 region q25–35 [25]. Although IL-15 mRNA can be found in many tissues and cells, including fibroblasts, muscle cells, keratinocytes, kidney cells, lymphocytes, mast cells, and tumor cells (reviewed in [26]), this four-helix-bundle cytokine is produced as a mature protein mainly by dendritic cells, monocytes, macrophages, and stromal cells, but not T cells ([27], [28] and reviewed in [24]). The discrepancy between the broad appearance of IL-15 mRNA

IL-15 trans-presentation and signaling

The prevailing mechanism of IL-15 action seems to be trans-presentation (juxtacrine signaling) (Fig. 1), although it also includes intracrine, autocrine, paracrine, and endocrine signaling ([40], [41] and reviewed in [26]). Cis-presentation, when IL-15 from autocrine or other sources is presented by IL-15Rα to IL-15R on the same cell, is also possible [42]. IL-15-producing cells, monocytes and dendritic cells in particular, simultaneously express the IL-15Rα chain, which, in contrast to IL-2Rα,

IL-15 bioactivity

Interleukin 15 plays an important role in the development, homeostasis and function of memory CD8+ T cells, NK cells, NKT cells, and intestinal intraepithelial T cells ([10], [71] and reviewed in [55]). It also induces proliferation of naïve CD8+ and memory CD4+ and CD8+ T cells [13], [52], promoting development of the primary response of effector CD8+ T cells [52], [72], and makes both CD4+ and CD8+ T cells resistant to the action of Treg cells [23]. IL-15 has also demonstrated chemotactic

Antitumor effects of interleukin 15

The ability of interleukin 15 to activate many immune antitumor mechanisms (Fig. 2) makes it a good candidate for application in tumor therapy. The most important cells engaged in IL-15 antitumor activity seem to be T cells, in particular CD8+ T cytotoxic cells and NK cells. Both of them can kill tumor cells by granule- or FAS-mediated pathways (reviewed in [95]). During the immune response, CD8+ T cells proceed through several stages, including activation of naïve cells, proliferation and

Application of IL-15 in experimental tumor therapy and attempts to potentiate its antitumor effects

IL-15's ability to stimulate the development and activity of effector and memory CD8+ T cells, NK and NKT cells, which all contribute significantly to the effectiveness of the antitumor immune response, raises hopes that it could become a valuable adjuvant in tumor immunotherapy.

In various experimental tumor models, IL-15 has demonstrated either no effect [52], marginal effect [119], or a significant therapeutic activity [6], [120], [121], [122], depending on the tumor and the experimental

Potential side effects of IL-15 in tumor immunotherapy

“Il n’ya pas de roses sans épines”. Although it is probably less toxic than IL-2 [21], considering the pleiotropic and sometimes even opposing effects that IL-15 exerts on many types of immune and non-immune cells [94], its application might be accompanied by the appearance of deleterious effects (Table 2). IL-15 can trigger a cytokine cascade including TNF-α, IL-1, IL-6, GM-CSF, and pro-inflammatory chemokines [61], [78]. It can also activate self-reactive T lymphocytes [154] and participate

Conclusions and perspectives

The ability of IL-15 to effectively strengthen numerous mechanisms of antitumor immunity both in vitro and in experimental tumor models has resulted in this cytokine being placed at the top of the list of the most promising immunotherapy drugs by the National Cancer Institute [24]. However, it should not be forgotten that the antitumor effects of IL-15 in some experimental tumor models were rather limited. These mechanisms partially overlap with those exerted by other members of the γc family

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

Jakub Golab is a recipient of the Mistrz Award from the Foundation for Polish Science and a member of the TEAM Program co-financed by the Foundation for Polish Science and the EU European Regional Development Fund. His studies are supported by the European Regional Development Fund through Innovative Economy grant POIG.01.01.02-00-008/08. Some of the figures were produced using Servier Medical Art (www.servier.com), for which the authors would like to acknowledge Servier.

Marek Jakobisiak is a professor of immunology at the Medical University of Warsaw, Poland. He graduated from and obtained his MD, PhD at the Medical University of Warsaw and conducted his postdoctoral research at the Wayne State University, Detroit, University of Alberta, Edmonton, and Memorial Sloan-Kettering Cancer Institute for Cancer Research, New York. After his return from the USA he established Department of Immunology in the Center of Biostructure Research at the Medical University of

References (172)

  • H. Krause et al.

    Genomic structure and chromosomal localization of the human interleukin 15 gene (IL-15)

    Cytokine

    (1996)
  • Y. Tagaya et al.

    IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels

    Immunity

    (1996)
  • T. Musso et al.

    Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15

    Blood

    (1999)
  • G. Kurys et al.

    The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15

    J Biol Chem

    (2000)
  • S.K. Olsen et al.

    Crystal structure of the interleukin-15.interleukin-15 receptor alpha complex: insights into trans and cis presentation

    J Biol Chem

    (2007)
  • D.M. Anderson et al.

    Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes

    J Biol Chem

    (1995)
  • S. Dubois et al.

    IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells

    Immunity

    (2002)
  • K.S. Schluns et al.

    The roles of interleukin-15 receptor alpha: trans-presentation, receptor component, or both?

    Int J Biochem Cell Biol

    (2005)
  • S. Sanjabi et al.

    Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells

    Immunity

    (2009)
  • E. Bulanova et al.

    Soluble Interleukin IL-15Ralpha is generated by alternative splicing or proteolytic cleavage and forms functional complexes with IL-15

    J Biol Chem

    (2007)
  • J.X. Lin et al.

    The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15

    Immunity

    (1995)
  • H. Shibuya et al.

    IL-2 and EGF receptors stimulate the hematopoietic cell cycle via different signaling pathways: demonstration of a novel role for c-myc

    Cell

    (1992)
  • P.P. McDonald et al.

    Interleukin-15 (IL-15) induces NF-kappaB activation and IL-8 production in human neutrophils

    Blood

    (1998)
  • Y. Minami et al.

    Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway

    Immunity

    (1995)
  • J.P. Lodolce et al.

    IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation

    Immunity

    (1998)
  • R. Badolato et al.

    Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic protein 1 production in human monocytes

    Blood

    (1997)
  • D. Girard et al.

    Differential effects of interleukin-15 (IL-15) and IL-2 on human neutrophils: modulation of phagocytosis, cytoskeleton rearrangement, gene expression, and apoptosis by IL-15

    Blood

    (1996)
  • M. Pelletier et al.

    Mechanisms involved in interleukin-15-induced suppression of human neutrophil apoptosis: role of the anti-apoptotic Mcl-1 protein and several kinases including Janus kinase-2, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases-1/2

    FEBS Lett

    (2002)
  • V. Budagian et al.

    IL-15/IL-15 receptor biology: a guided tour through an expanding universe

    Cytokine Growth Factor Rev

    (2006)
  • E. Lugli et al.

    Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

    Blood

    (2010)
  • E. Mortier et al.

    Macrophage- and dendritic-cell-derived interleukin-15 receptor alpha supports homeostasis of distinct CD8+ T cell subsets

    Immunity

    (2009)
  • K.H. Grabstein et al.

    Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor

    Science

    (1994)
  • S.A. Rosenberg et al.

    Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2

    J Am Med Assoc

    (1994)
  • G. Fyfe et al.

    Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy

    J Clin Oncol

    (1995)
  • M. Rosenstein et al.

    Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin 2

    J Immunol

    (1986)
  • M. Zhang et al.

    Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer

    Proc Natl Acad Sci USA

    (2009)
  • K.K. Hoyer et al.

    Interleukin-2 in the development and control of inflammatory disease

    Immunol Rev

    (2008)
  • Z. Dai et al.

    The role of the common cytokine receptor gamma-chain in regulating IL-2-dependent, activation-induced CD8+ T cell death

    J Immunol

    (1999)
  • M.K. Kennedy et al.

    Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice

    J Exp Med

    (2000)
  • S. Dubois et al.

    Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action

    J Immunol

    (2008)
  • M. Berard et al.

    IL-15 promotes the survival of naive and memory phenotype CD8+ T cells

    J Immunol

    (2003)
  • M.M. Sandau et al.

    IL-15 regulates both quantitative and qualitative features of the memory CD8 T cell pool

    J Immunol

    (2010)
  • K.B. Vang et al.

    IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+ Foxp3+ regulatory T cell development

    J Immunol

    (2008)
  • M. Ben Ahmed et al.

    IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway

    J Immunol

    (2009)
  • M.A. Cheever

    Twelve immunotherapy drugs that could cure cancers

    Immunol Rev

    (2008)
  • S. Bulfone-Paus et al.

    The interleukin-15/interleukin-15 receptor system as a model for juxtacrine and reverse signaling

    Bioessays

    (2006)
  • W.E. Carson et al.

    Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro

    J Clin Invest

    (1995)
  • H. Jonuleit et al.

    Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells: a role for IL-15 in attraction of T cells

    J Immunol

    (1997)
  • R.N. Bamford et al.

    The 5′ untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control

    J Immunol

    (1998)
  • G.G. Neely et al.

    Lipopolysaccharide-stimulated or granulocyte-macrophage colony-stimulating factor-stimulated monocytes rapidly express biologically active IL-15 on their cell surface independent of new protein synthesis

    J Immunol

    (2001)
  • Cited by (100)

    View all citing articles on Scopus

    Marek Jakobisiak is a professor of immunology at the Medical University of Warsaw, Poland. He graduated from and obtained his MD, PhD at the Medical University of Warsaw and conducted his postdoctoral research at the Wayne State University, Detroit, University of Alberta, Edmonton, and Memorial Sloan-Kettering Cancer Institute for Cancer Research, New York. After his return from the USA he established Department of Immunology in the Center of Biostructure Research at the Medical University of Warsaw, where he was the head of department until 2009. His research interests are concentrated on experimental tumor therapy.

    Jakub Golab obtained his MD at the Medical University of Warsaw in Poland in 1997. He has a PhD degree received from the same university in 1998. He conducted his postdoctoral research in Beth Israel Deaconess Medical Center, Harvard Institutes of Health, Boston and at the University of Texas, Southwestern Medical School. Since 2009 he is a head of the Department of Immunology, at the Medical University of Warsaw.

    Witold Lasek was graduated from Medical University of Warsaw in 1981, completed his PhD on “NK cell activity in healthy subjects” at the Medical University of Warsaw, Poland, in 1985. Currently, he is professor of immunology in the Department of Immunology, Center of Biostructre Research, Medical University of Warsaw – he teaches immunology to undergraduate and graduate students at this University. Together with M. Jakobisiak, J. Golab, and T. Stokłosa he is the co-editor of “IMMUNOLOGY” – the best-selling textbook of immunology in Poland (the 6th edition in preparation). The main area of his research activity is tumor immunology and immunotherapy. He focuses on developing new experimental therapeutic approaches for the treatment of cancer, including cytokine and gene therapy. Now, he directs research program concerning application of dendritic cells in tumor immunotherapy in a melanoma model in mice.

    View full text