Abstract
Interleukin-15 (IL-15) is a gamma-C (γC) cytokine that stimulates the differentiation and proliferation of T, B, and natural killer (NK) cells. Many clinical and preclinical studies have focused on exploiting memory CD8 T cells and NK cells to treat cancer due to their ability to recognize tumor cells, be rapidly activated, and produce many antitumor cytokines, cytotoxic granules, and surface ligands that promote cell death. Memory CD8 T and NK cells respond robustly to IL-15 compared to naive and effector T cells and are thought to be the primary target of IL-15’s function in vivo. In response to IL-15 or therapeutic soluble IL-15/IL15 receptor complexes, CD8 T cells and NK cells increase production of cytotoxic granules and migratory capacity which promotes antitumor immunity. Thus, IL-15 plays a critical role in the immune system’s ability to eliminate tumor cells and has proved to be a promising target for cancer immunotherapy.
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References
Bergamaschi C, Rosati M, Jalah R, et al. Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity. J Biol Chem. 2008;283:4189–99.
Bergamaschi C, Bear J, Rosati M, et al. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse serum. Blood. 2012;120:e1–8.
Berger C, Berger M, Hackman RC, et al. Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood. 2009;114:2417–26.
Berzofsky JA. A push-pull vaccine strategy using toll-like receptor ligands, IL-15, and blockade of negative regulation to improve the quality and quantity of T cell immune responses. Vaccine. 2012;30:4323–7.
Bessard A, Sole V, Bouchaud G, Quemener A, Jacques Y. High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor alpha fusion protein, in metastatic melanoma and colorectal cancer. Mol Cancer Ther. 2009;8:2736–45.
Chen J, Petrus M, Bamford R, et al. Increased serum soluble IL-15Ralpha levels in T-cell large granular lymphocyte leukemia. Blood. 2012;119:137–43.
Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity. 2002;17:537–47.
Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26:5233–9.
Grabstein KH, Eisenman J, Shanebeck K, et al. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994;264:965–8.
Klebanoff CA, Finkelstein SE, Surman DR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci U S A. 2004;101:1969–74.
Kobayashi H, Dubois S, Sato N, et al. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immuno surveillance. Blood. 2005;105:721–7.
Liu D, Song L, Wei J, et al. IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity. J Clin Invest. 2012;122:2221–33.
Mattei F, Schiavoni G, Belardelli F, Tough DF. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol. 2001;167:1179–87.
Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105:3051–7.
Muller D. Targeted cancer immunotherapy: mimicking physiological trans-presentation of IL-15. Oncoimmunology. 2012;1:1213–4.
Oh S, Berzofsky JA, Burke DS, Waldmann TA, Perera LP. Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc Natl Acad Sci U S A. 2003;100:3392–7.
Pappa C, Miyakis S, Tsirakis G, et al. Serum levels of interleukin-15 and interleukin-10 and their correlation with proliferating cell nuclear antigen in multiple myeloma. Cytokine. 2007;37:171–5.
Porrata LF, Inwards DJ, Micallef IN, et al. Interleukin-15 affects patient survival through natural killer cell recovery after autologous hematopoietic stem cell transplantation for non-Hodgkin lymphomas. Clin Dev Immunol. 2010;2010:914945.
Rubinstein MP, Kovar M, Purton JF, et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A. 2006;103:9166–71.
Schwartz RN, Stover L, Dutcher J. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park). 2002;16:11–20.
Sneller MC, Kopp WC, Engelke KJ, et al. IL-15 administered by continuous infusion to rhesus macaques induces massive expansion of CD8+ T effector memory population in peripheral blood. Blood. 2011;118:6845–8.
Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci. 2012;33:35–41.
Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol. 2006;177:6072–80.
Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M. Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother. 2010;59:73–9.
Teague RM, Sather BD, Sacks JA, et al. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med. 2006;12:335–41.
Thiant S, Yakoub-Agha I, Magro L, et al. Plasma levels of IL-7 and IL-15 in the first month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. Bone Marrow Transplant. 2010;45:1546–52.
Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6:595–601.
Waldmann TA, Lugli E, Roederer M, et al. Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques. Blood. 2011;117:4787–95.
Wang X, Lupardus P, Laporte SL, Garcia KC. Structural biology of shared cytokine receptors. Annu Rev Immunol. 2009;27:29–60.
Zhang X, Sun S, Hwang I, Tough DF, Sprent J. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity. 1998;8:591–9.
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Marzo, A.L., Sowell, R.T. (2017). Interleukin-15. In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0717-2_60
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DOI: https://doi.org/10.1007/978-1-4419-0717-2_60
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