Interleukin-15

Reference work entry

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.

Keywords

Interleukin-15 Metastatic renal cell carcinoma Malignant melanoma Cytokine therapy Adoptive cell therapy NK cells T cells 

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Berger C, Berger M, Hackman RC, et al. Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood. 2009;114:2417–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. Muller D. Targeted cancer immunotherapy: mimicking physiological trans-presentation of IL-15. Oncoimmunology. 2012;1:1213–4.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Schwartz RN, Stover L, Dutcher J. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park). 2002;16:11–20.Google Scholar
  21. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci. 2012;33:35–41.CrossRefPubMedGoogle Scholar
  23. Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol. 2006;177:6072–80.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6:595–601.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Wang X, Lupardus P, Laporte SL, Garcia KC. Structural biology of shared cytokine receptors. Annu Rev Immunol. 2009;27:29–60.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department Immunology-MicrobiologyRush University-Medical CenterChicagoUSA
  2. 2.Department of ImmunobiologyYale University School of MedicineNew HavenUSA

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