Interleukin-15 biology and its therapeutic implications in cancer

doi:10.1016/j.tips.2011.09.004

Trends in Pharmacological Sciences

Volume 33, Issue 1, January 2012, Pages 35-41

https://doi.org/10.1016/j.tips.2011.09.004 Get rights and content

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.

Section snippets

Interleukin-15

In the past decade immunotherapy has moved to the forefront of cancer research with promising results recently reported in a number of high profile clinical trials. This has led to the approval of a first-in-class vaccine for the treatment of castrate-resistant prostate cancer, and the approval of an immunostimulatory monoclonal antibody for the treatment of advanced melanoma 1, 2. Importantly, patients receiving these novel agents, sipuleucel-T or ipilimumab, have for the first time

Molecular biology

IL-15 is a 14–15 kDa glycoprotein encoded by a 34 kb region on chromosome 4q31 (Figure 1). The human IL15 gene comprises nine exons and eight introns, four of which (exons 5 through 8) code for the mature protein [11]. There are two isoforms of IL-15 mRNA that differ in their signal peptides lengths. The originally identified isoform 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

IL-15 expression

IL-15 mRNA is expressed by a large number of tissues including fibroblasts, keratinocytes, epithelial cells of various tissues, nerve cells, monocytes, macrophages and dendritic cells [13]. Low levels of mRNA have also been detected in T-cells [7]. Although IL-15 mRNA expression is widespread, detection of IL-15 protein is largely limited to monocytes/macrophages and dendritic cells. This indicates that, although regulation of IL-15 protein production occurs at the transcription, translation

Interleukin-15 receptor

The heterotrimeric IL-15 receptor is composed of a β subunit (IL-2R/15Rβ) that is shared with the IL-2 receptor, a common γ subunit (γc) shared with IL-2, IL-4, IL-7, IL-9 and IL-21, and a unique α subunit (IL-15Rα) that confers receptor specificity to IL-15 [15]. The IL-2R/15Rβ subunit is a 525 amino acid receptor consisting of a 214 amino acid extracellular segment, a 25 amino acid transmembrane (TM) region, and a 286 amino acid cytoplasmic domain [16]. The human γc consists of a 233 amino

Molecular biology of IL-15Rα

The human IL-15Rα gene maps to chromosome 10 and is made up of seven exons, which, as a result of alternative splicing, can produce eight different isoforms of IL-15Rα [18]. In humans there are three types of splicing events: (i) alternative usage of exon 7 or 7′; (ii) deletion of exon 3 encoding the linker region, and (iii) deletion of exon 2 which encodes the Sushi domain resulting in an inability to bind IL-15 [18]. Exon 2 also has a putative nuclear localization signal, the deletion of

Interaction of Interleukin-15 with its receptor

IL-15Rα is widely expressed in humans and mice independently of IL-2R/IL-15Rβ–γc [9]. It binds to IL-15 with high affinity (K_d >10^–11 M) and retains IL-15 on the cell surface. IL-15Rα trans-presents IL-15 to IL-2R/15Rβ-γc on nearby effector NK and T cells by the formation of an immunological synapse (Figure 2) 19, 20. This immunological synapse mechanism is believed to limit exposure to circulating IL-15, restricting aberrant immune stimulation and decreasing the risk of autoimmunity from

Biological effects of interleukin-15

IL-15 was initially identified for its ability to stimulate T cell proliferation in an IL-2-like manner through common receptor components (IL-2R/15Rβ–γc) and signaling through JAK1/JAK3 and STAT3/STAT5. Similarly to IL-2, IL-15 has been shown to stimulate the proliferation of activated CD4^–CD8^–, CD4⁺CD8⁺, CD4⁺ and CD8⁺ T cells as well as facilitate the induction of cytotoxic T-lymphocytes, and the generation, proliferation and activation of NK cells [7]. However, unlike IL-2 which is required

Interleukin-15 and cancer

As a potent proinflammatory cytokine, IL-15 plays an important and complex role in autoimmune disease and inflammation. There is increasing recognition of a link between inflammation and the development of cancer [36]. Because IL-15 stimulates the proliferation and maintenance of NK cells, B and T lymphocytes, it is probable that IL-15 could play a role in some hematological malignancies. In support, proliferation of the murine T cell lymphoma cell line LBC is enhanced by IL-15 [37] and

Preclinical studies

The direct administration of IL-15 has shown anti-tumor effects in several preclinical mouse tumor models 10, 49, 50, 51. In a recent study by Yu et al., IL-15 was shown to prolong the survival of mice with metastatic CT26 colon cancer [51]. However, administration of IL-15 alone was not optimal because it also activated immune-system negative regulatory checkpoints that might also dampen the immune response. IL-15 induced the expression of the immunosuppressive receptor, programmed death-1

IL-15 toxicology

IL-15 plays an important role in autoimmune diseases and inflammation. Diseases that manifest elevated IL-15 levels, disordered expression, or abnormal IL-15 signaling include pemphigus vulgaris, rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, multiple sclerosis, celiac disease, as well as inflammatory bowel disease [56]. IL-15 has been hypothesized to sit at the apex of a pyramid of proinflammatory cytokines that includes TNFα, IL-1β, IL-6, IL-8, granulocyte-macrophage colony

Clinical trials of IL-15

To date there have been seven clinical trials initiated using IL-15 (Table 1). These trials are either ongoing or recently completed and have yet to be published. Of these trials, four targeted cancer with the remaining three targeting HIV infections. Two of the cancer trials use rhIL-15 protein administered either alone (www.clinicaltrials.gov: NCT01021059), or combined with the administration of patient-derived tumor-infiltrating lymphocytes (TIL) (www.clinicaltrials.gov: NCT01369888). The

Concluding remarks

The broad immunological activity coupled with an apparent lack of toxicity seen in preclinical studies makes IL-15 an exciting candidate for cancer therapy. The similarity it shares with IL-2 has led to the speculation that it might be effective in cancers in which IL-2 has been effective (i.e. renal cancer and melanoma), and to date these are the cancers being examined in the first clinical trials of IL-15. Improved safety while retaining or improving efficacy, when compared to IL-2, would

Acknowledgments

This work is supported in part by the Division of Hematology–Oncology, University of Cincinnati and the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health (NIH). T.A.W. holds a U.S. government patent on monoclonal antibodies that target IL-2R/Il-15Rβγ and a patent application for expansion of natural killer and CD8 T cells with IL-15R/ligand activator complexes.

References (59)

C. Berger
Safety and immunologic effects of IL-15 administration in nonhuman primates
Blood
(2009)
W. Munger
Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2
Cell. Immunol.
(1995)
H. Krause
Genomic structure and chromosomal localization of the human interleukin 15 gene (IL-15)
Cytokine
(1996)
D.M. Anderson
Functional characterization of human interleukin 15 receptor α chain and close linkage of IL-15RA and IL-2RA genes
J. Biol. Chem.
(1995)
S. Dubois
Natural splicing of exon 2 of human interleukin-15 receptor alpha-chain mRNA results in a shortened form with a distinct pattern of expression
J. Biol. Chem.
(1999)
S. Dubois
IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells
Immunity
(2002)
H. Kobayashi
Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance
Blood
(2005)
V. Budagian
IL-15/IL-15 receptor biology: a guided tour through an expanding universe
Cytokine Growth Factor Rev.
(2006)
H. Kanegane et al.
Activation of naive and memory T cells by interleukin-15
Blood
(1996)
J.P. Lodolce
IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation
Immunity
(1998)

M. Pelletier

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)

M. Figueras

Interleukin-15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour-bearing rats

FEBS Lett.

(2004)

A.L. Angiolillo

Interleukin-15 promotes angiogenesis in vivo

Biochem. Biophys. Res. Commun.

(1997)

U.K. Hanisch

Mouse brain microglia express interleukin-15 and its multimeric receptor complex functionally coupled to Janus kinase activity

J. Biol. Chem.

(1997)

N. Sato

Development of an IL-15-autocrine CD8 T-cell leukemia in IL-15-transgenic mice requires the cis expression of IL-15Rα

Blood

(2011)

S. Yamasaki

Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling

Leuk. Res.

(2004)

L. Trentin

Interleukin-15 promotes the growth of leukemic cells of patients with B-cell chronic lymphoproliferative disorders

Blood

(1996)

L.S. Quinn

Serum and muscle interleukin-15 levels decrease in aging mice: correlation with declines in soluble interleukin-15 receptor alpha expression

Exp. Gerontol.

(2010)

A. Di Sabatino

Role of IL-15 in immune-mediated and infectious diseases

Cytokine Growth Factor Rev.

(2011)

E. Lugli

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

Blood

(2010)

T.A. Waldmann

Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques

Blood

(2011)

P.W. Kantoff

Sipuleucel-T immunotherapy for castration-resistant prostate cancer

N. Engl. J. Med.

(2010)

F.S. Hodi

Improved survival with Ipilimumab in patients with metastatic melanoma

N. Engl. J. Med.

(2010)

S. Mocellin

Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis

J. Natl. Cancer Inst.

(2010)

A.A. Tarhini et al.

Interleukin-2 for the treatment of melanoma

Curr. Opin. Investig. Drugs.

(2005)

J.D. Burton

A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells

Proc. Natl. Acad. Sci. U.S.A.

(1994)

K.H. Grabstein

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

Science

(1994)

T.A. Waldmann et al.

The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens

Annu. Rev. Immunol.

(1999)

J. Marks-Konczalik

IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice

Proc. Natl. Acad. Sci. U.S.A.

(2000)

Cited by (298)

The role of inflammatory mediators and matrix metalloproteinases (MMPs) in the progression of osteoarthritis
2024, Biomaterials and Biosystems
Osteoarthritis (OA) is a chronic musculoskeletal disorder characterized by an imbalance between (synthesis) and catabolism (degradation) in altered homeostasis of articular cartilage mediated primarily by the innate immune system. OA degenerates the joints resulting in synovial hyperplasia, degradation of articular cartilage with damage of the structural and functional integrity of the cartilage extracellular matrix, subchondral sclerosis, osteophyte formation, and is characterized by chronic pain, stiffness, and loss of function. Inflammation triggered by factors like biomechanical stress is involved in the development of osteoarthritis. In OA apart from catabolic effects, anti-inflammatory anabolic processes also occur continually. There is also an underlying chronic inflammation present, not only in cartilage tissue but also within the synovium, which perpetuates tissue destruction of the OA joint. The consideration of inflammation in OA considers synovitis and/or other cellular and molecular events in the synovium during the progression of OA. In this review, we have presented the progression of joint degradation that results in OA. The critical role of inflammation in the pathogenesis of OA is discussed in detail along with the dysregulation within the cytokine networks composed of inflammatory and anti-inflammatory cytokines that drive catabolic pathways, inhibit matrix synthesis, and promote cellular apoptosis. OA pathogenesis, fluctuation of synovitis, and its clinical impact on disease progression are presented here along with the role of synovial macrophages in promoting inflammatory and destructive responses in OA. The role of interplay between different cytokines, structure, and function of their receptors in the inter-cellular signaling pathway is further explored. The effect of cytokines in the increased synthesis and release of matrix-decomposing proteolytic enzymes, such as matrix metalloproteinase (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motif (ADAMTS), is elaborated emphasizing the potential impact of MMPs on the chondrocytes, synovial cells, articular and periarticular tissues, and other immune system cells migrating to the site of inflammation. We also shed light on the pathogenesis of OA via oxidative damage particularly due to nitric oxide (NO) via its angiogenic response to inflammation. We concluded by presenting the current knowledge about the tissue inhibitors of metalloproteinases (TIMPs). Synthetic MMP inhibitors include zinc binding group (ZBG), non-ZBG, and mechanism-based inhibitors, all of which have the potential to be therapeutically beneficial in the treatment of osteoarthritis. Improving our understanding of the signaling pathways and molecular mechanisms that regulate the MMP gene expression, may open up new avenues for the creation of therapies that can stop the joint damage associated with OA.
FOLFIRINOX chemotherapy modulates the peripheral immune landscape in pancreatic cancer: Implications for combination therapies and early response prediction
2024, European Journal of Cancer
FOLFIRINOX chemotherapy has improved outcomes for pancreatic cancer patients, but poor long-term survival outcomes and high toxicity remain challenges. This study investigates the impact of FOLFIRINOX on plasma proteins and peripheral immune cells to guide immune-based combination therapies and, ideally, to identify a potential biomarker to predict early disease progression during FOLFIRINOX.
Blood samples were collected from 86 pancreatic cancer patients before and two weeks after the first FOLFIRINOX cycle and subjected to comprehensive immune cell and proteome profiling. Principal Component Analysis and Linear Mixed Effect Regression models were used for data analysis. FOLFIRINOX efficacy was radiologically evaluated after the fourth cycle.
One cycle of FOLFIRINOX diminished tumour-cell-related pathways and enhanced pathways related to immune activation, illustrated by an increase in pro-inflammatory IL–18, IL–15, and TNFRSF4. Similarly, FOLFIRINOX promoted the activation of CD4 + and CD8 + T cells, the proliferation of NK(T), and the activation of antigen-presenting cells. Furthermore, high pre-treatment levels of VEGFA and PRDX3 and an elevation in FCRL3 levels after one cycle predicted early progression under FOLFIRINOX. Finally, patients with progressive disease exhibited high levels of inhibitory markers on B cells and CD8 + T cells, while responding patients exhibited high levels of activation markers on CD4 + and CD8 + T cell subsets.
FOLFIRINOX has immunomodulatory effects, providing a foundation for clinical trials exploring immune-based combination therapies that harness the immune system to treat pancreatic cancer. In addition, several plasma proteins hold potential as circulating predictive biomarkers for early prediction of FOLFIRINOX response in patients with pancreatic cancer.
Engineering enhanced chimeric antigen receptor-T cell therapy for solid tumors
2023, Immuno-Oncology and Technology
The early clinical success and subsequent US Food and Drug Administration approval of chimeric antigen receptor (CAR)-T cell therapy for leukemia and lymphoma affirm that engineered T cells can be a powerful treatment for hematologic malignancies. Yet this success has not been replicated in solid tumors. Numerous challenges emerged from clinical experience and well-controlled preclinical animal models must be met to enable safe and efficacious CAR-T cell therapy in solid tumors. Here, we review recent advances in bioengineering strategies developed to enhance CAR-T cell therapy in solid tumors, focusing on targeted single-gene perturbation, genetic circuits design, cytokine engineering, and interactive biomaterials. These bioengineering approaches present a unique set of tools that synergize with CAR-T cells to overcome obstacles in solid tumors and achieve robust and long-lasting therapeutic efficacy.
Cytokines and their role as immunotherapeutics and vaccine Adjuvants: The emerging concepts
2023, Cytokine
Cytokines are a protein family comprising interleukins, lymphokines, chemokines, monokines and interferons. They are significant constituents of the immune system, and they act in accordance with specific cytokine inhibiting compounds and receptors for the regulation of immune responses. Cytokine studies have resulted in the establishment of newer therapies which are being utilized for the treatment of several malignant diseases. The advancement of these therapies has occurred from two distinct strategies. The first strategy involves administrating the recombinant and purified cytokines, and the second strategy involves administrating the therapeutics which inhibits harmful effects of endogenous and overexpressed cytokines. Colony stimulating factors and interferons are two exemplary therapeutics of cytokines. An important effect of cytokine receptor antagonist is that they can serve as anti-inflammatory agents by altering the treatments of inflammation disorder, therefore inhibiting the effects of tumour necrosis factor. In this article, we have highlighted the research behind the establishment of cytokines as therapeutics and vaccine adjuvants, their role of immunotolerance, and their limitations.
Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response
2023, Molecular Therapy Oncolytics
We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer.
Biomaterial-based platforms for modulating immune components against cancer and cancer stem cells
2023, Acta Biomaterialia
Immunotherapy involves the therapeutic alteration of the patient's immune system to identify, target, and eliminate cancer cells. Dendritic cells, macrophages, myeloid-derived suppressor cells, and regulatory T cells make up the tumor microenvironment. In cancer, these immune components (in association with some non-immune cell populations like cancer-associated fibroblasts) are directly altered at a cellular level. By dominating immune cells with molecular cross-talk, cancer cells can proliferate unchecked. Current clinical immunotherapy strategies are limited to conventional adoptive cell therapy or immune checkpoint blockade. Targeting and modulating key immune components presents an effective opportunity. Immunostimulatory drugs are a research hotspot, but their poor pharmacokinetics, low tumor accumulation, and non-specific systemic toxicity limit their use. This review describes the cutting-edge research undertaken in the field of nanotechnology and material science to develop biomaterials-based platforms as effective immunotherapeutics. Various biomaterial types (polymer-based, lipid-based, carbon-based, cell-derived, etc.) and functionalization methodologies for modulating tumor-associated immune/non-immune cells are explored. Additionally, emphasis has been laid on discussing how these platforms can be used against cancer stem cells, a fundamental contributor to chemoresistance, tumor relapse/metastasis, and failure of immunotherapy. Overall, this comprehensive review strives to provide up-to-date information to an audience working at the juncture of biomaterials and cancer immunotherapy.
Cancer immunotherapy possesses incredible potential and has successfully transitioned into a clinically lucrative alternative to conventional anti-cancer therapies. With new immunotherapeutics getting rapid clinical approval, fundamental problems associated with the dynamic nature of the immune system (like limited clinical response rates and autoimmunity-related adverse effects) have remained unanswered. In this context, treatment approaches that focus on modulating the compromised immune components within the tumor microenvironment have garnered significant attention amongst the scientific community. This review aims to provide a critical discussion on how various biomaterials (polymer-based, lipid-based, carbon-based, cell-derived, etc.) can be employed along with immunostimulatory agents to design innovative platforms for selective immunotherapy directed against cancer and cancer stem cells.

View all citing articles on Scopus

View full text

Trends in Pharmacological Sciences

ReviewInterleukin-15 biology and its therapeutic implications in cancer

Section snippets

Interleukin-15

Molecular biology

IL-15 expression

Interleukin-15 receptor

Molecular biology of IL-15Rα

Interaction of Interleukin-15 with its receptor

Biological effects of interleukin-15

Interleukin-15 and cancer

Preclinical studies

IL-15 toxicology

Clinical trials of IL-15

Concluding remarks

Acknowledgments

Blood

Cell. Immunol.

Cytokine

J. Biol. Chem.

J. Biol. Chem.

Immunity

Blood

Cytokine Growth Factor Rev.

Blood

Immunity

FEBS Lett.

FEBS Lett.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Blood

Leuk. Res.

Blood

Exp. Gerontol.

Cytokine Growth Factor Rev.

Blood

Blood

Sipuleucel-T immunotherapy for castration-resistant prostate cancer

N. Engl. J. Med.

Improved survival with Ipilimumab in patients with metastatic melanoma

N. Engl. J. Med.

Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis

J. Natl. Cancer Inst.

Interleukin-2 for the treatment of melanoma

Curr. Opin. Investig. Drugs.

A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells

Proc. Natl. Acad. Sci. U.S.A.

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

Science

The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens

Annu. Rev. Immunol.

IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice

Proc. Natl. Acad. Sci. U.S.A.

Review
Interleukin-15 biology and its therapeutic implications in cancer