Abstract

Interleukin 15 is a pleiotropic cytokine of the four α helix bundle family. Binding to a heterotrimeric receptor complex, which consists of a unique, high affinity IL-15Rα-chain and IL-2/IL-15Rβ and IL-2Rγ chains, IL-15 activates signaling pathways leading to activation and proliferation of T and B cells, as well as natural killer cells. At the same time, IL-15 protects effector cells from T regulatory cells and does not induce immune tolerance. The significant regulatory action of IL-15 on the immune system provides new opportunities for development of anti-cancer therapies.As documented in many experiments using different tumor models, IL-15 enhances antitumor effects. To improve the efficiency of IL-15, several strategies, including combination with other anti-cancer therapies such as chemotherapy, additional use of antibodies (anti-PD-L1, anti-CTLA-4, anti-CD40), or other cytokines, have been evaluated. Increased anti-tumor activity can also be obtained by using IL-15 agonists.However, acting as a growth factor for immune cells but also for tumor cells, IL-15 may promote their proliferation, survival and dissemination. Of significance seems the role of IL-15 in the pathogenesis of hematological malignancies, which is due to the involvement in the proliferation and differentiation of NK, T and B cells.Currently, several experimental strategies are available to block biological activity of IL-15. Among compounds inhibiting the activity of IL-15 are not only monoclonal antibodies interacting directly with the cytokine or with IL-15R subunits, but also mutant forms of IL-15 and protein constructs.

References

• 1. Anderson D.M., Kumaki S., Ahdieh M., Bertles J., Tometsko M., Loomis A., Giri J., Copeland N.G., Gilbert D.J., Jenkins N.A., Valentine V., Shapiro D.N., Morris S.W., Park L.S., Cosman D.: Functional characterization of the human interleukin‑15 receptor α chain and close linkage of IL15RA and IL2RA genes. J. Biol. Chem., 1995; 270: 29862‑29869
  Google Scholar
• 2. Avice M.N., Demeure C.E., Delespesse G., Rubio M., Armant M., Sarfati M.: IL‑15 promotes IL‑12 production by human monocytes via T cell‑dependent contact and may contribute to IL‑12‑mediated IFN‑γ secretion by CD4+ T cells in the absence of TCR ligation. J. Immunol., 1998; 161: 3408‑3415
  Google Scholar
• 3. Azimi N., Brown K., Bamford r.N., Tagaya Y., Siebenlist U., Waldmann T.A.: Human T cell lymphotropic virus type I Tax protein trans‑activates interleukin 15 gene transcription through an NF‑κB site. Proc. Natl. Acad. Sci. USA, 1998; 95: 2452‑2457
  Google Scholar
• 4. Azzi S., Bruno S., Giron‑Michel J., Clay D., Devocelle A., Croce M., Ferrini S., Chouaib S., Vazquez A., Charpentier B.: Differentiation therapy: targeting human renal cancer stem cells with interleukin 15. J. Natl. Cancer Inst., 2011; 103: 1884‑1898
  Google Scholar
• 5. Badoual C., Bouchaud G., Agueznay Nel H., Mortier E., Hans S., Gey A., Fernani F., Peyrard S., Puig P.L., Bruneval P., Sastre X., Plet A., Garrigue‑Antar L., Quintin‑Colonna F., Fridman W.H., Brasnu D., Jacques Y., Tartour E.: The soluble α chain of interleukin‑15 receptor: a proinflammatory molecule associated with tumor progression in head and neck cancer. Cancer Res., 2008; 68: 3907‑3914
  Google Scholar
• 6. Bamford r.N., Battiata A.P., Burton J.D., Sharma H., Waldmann T.A.: Interleukin (IL) 15/IL‑T production by the adult T‑cell leukemia cell line HuT‑102 is associated with a human T‑cell lymphotrophic virus type I region/IL‑15 fusion message that lacks many upstream AUGs that normally attenuates IL‑15 mRNA translation. Proc. Natl. Acad. Sci. USA, 1996; 93: 2897‑2902
  Google Scholar
• 7. Bamford r.N., DeFilippis A.P., Azimi N., Kurys G., Waldmann T.A.: 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; 160: 4418‑4426
  Google Scholar
• 8. Barry M., Bleackley r.C.: Cytotoxic T lymphocytes: all roads lead to death. Nat. Rev. Immunol., 2002; 2: 401‑409
  Google Scholar
• 9. Becker J.C., Andersen M.H., Schrama D., Thor Straten P.: Immune‑suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother., 2013; 62: 1137‑1148
  Google Scholar
• 10. Ben Ahmed M., Belhadj Hmida N., Moes N., Buyse S., Abdeladhim M., Louzir H., Cerf‑Bensussan N.: IL‑15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3‑kinase pathway. J. Immunol., 2009; 182: 6763‑6770
  Google Scholar
• 11. Bernard J., Harb C., Mortier E., Quéméner A., Meloen r.H., Vermot‑Desroches C., Wijdeness J., van Dijken P., Grötzinger J., Slootstra J.W., Plet A., Jacques Y.: Identification of an interleukin‑15α receptor‑binding site on human interleukin‑15. J. Biol. Chem., 2004; 279: 24313‑24322
  Google Scholar
• 12. Bessard A., Solé V., Bouchaud G., Quéméner A., Jacques Y.: High antitumor activity of RLI, an interleukin‑15 (IL‑15)‑IL‑15 receptor α fusion protein, in metastatic melanoma and colorectal cancer. Mol. Cancer Ther., 2009; 8: 2736‑2745
  Google Scholar
• 13. Budagian V., Bulanova E., Paus r., Bulfone‑Paus S.: IL‑15/IL‑15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev., 2006; 17: 259‑280
  Google Scholar
• 14. Bulfone‑Paus S., Bulanova E., Budagian V., Paus r.: The interleukin‑15/interleukin‑15 receptor system as a model for juxtacrine and reverse signaling. Bioessays, 2006; 28: 362‑377
  Google Scholar
• 15. Cao S., Troutt A.B., Rustum Y.M.: Interleukin 15 protects against toxicity and potentiates antitumor activity of 5‑fluorouracil alone and in combination with leucovorin in rats bearing colorectal cancer. Cancer Res., 1998; 58: 1695‑1699
  Google Scholar
• 16. Carson W.E., Ross M.E., Baiocchi r.A., Marien M.J., Boiani N., Grabstein K., Caligiuri M.A.: 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; 96: 2578‑2582
  Google Scholar
• 17. Chen J., Petrus M., Bamford r., Shih J.H., Morris J.C., Janik J.E., Waldmann T.A.: Increased serum soluble IL‑15Rα levels in T‑cell large granular lymphocyte leukemia. Blood, 2012; 119: 137‑143
  Google Scholar
• 18. Dubois S., Magrangeas F., Lehours P., Raher S., Bernard J., Boisteau O., Leroy S., Minvielle S., Godard A., Jacques Y.: Natural splicing of exon 2 of human interleukin‑15 receptor α‑chain mRNA results in a shortened form with a distinct pattern of expression. J. Biol. Chem., 1999; 274: 26978‑26984
  Google Scholar
• 19. Dubois S., Mariner J., Waldmann T.A., Tagaya Y.: IL‑15Rα recycles and presents IL‑15 In trans to neighboring cells. Immunity, 2002; 17: 537‑547
  Google Scholar
• 20. Dubois S., Patel H.J., Zhang M., Waldmann T.A., Müller J.R.: Preassociation of IL‑15 with IL‑15Rα‑IgG1‑Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J. Immunol., 2008; 180: 2099‑2106
  Google Scholar
• 21. Fehniger T.A., Caligiuri M.A.: Interleukin 15: biology and relevance to human disease. Blood, 2001; 97: 14‑32
  Google Scholar
• 22. Ferrari‑Lacraz S., Zanelli E., Neuberg M., Donskoy E., Kim Y.S., Zheng X.X., Hancock W.W., Maslinski W., Li X.C., Strom T.B., Moll T.: Targeting IL‑15 receptor‑bearing cells with an antagonist mutant IL‑15/Fc protein prevents disease development and progression in murine collagen‑induced arthritis. J. Immunol., 2004; 173: 5818‑5826
  Google Scholar
• 23. Giri J.G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L.S., Cosman D., Anderson D.: Utilization of the beta and gamma chains of the IL‑2 receptor by the novel cytokine IL‑15. EMBO J., 1994; 13: 2822‑2830
  Google Scholar
• 24. Giri J.G., Kumaki S., Ahdieh M., Friend D.J., Loomis A., Shanebeck K., DuBose r., Cosman D., Park L.S., Anderson D.M.: Identification and cloning of a novel IL‑15 binding protein that is structurally related to the alpha chain of the IL‑2 receptor. EMBO J., 1995; 14: 3654‑3663
  Google Scholar
• 25. Giron‑Michel J., Azzi S., Khawam K., Mortier E., Caignard A., Devocelle A., Ferrini S., Croce M., Francois H., Lecru L., Charpentier B., Chouaib S., Azzarone B., Eid P.: Interleukin‑15 plays a central role in human kidney physiology and cancer through the gc signaling pathway. PLoS One, 2012; 7: e31624
  Google Scholar
• 26. Gomes‑Giacoia E., Miyake M., Goodison S., Sriharan A., Zhang G., You L., Egan J.O., Rhode P.R., Parker A.S., Chai K.X., Wong H.C., Rosser C.J.: Intravesical ALT‑803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion. PLoS One, 2014; 9: e96705
  Google Scholar
• 27. Grabstein K.H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M.A., Ahdieh M. i wsp.: Cloning of a T cell growth factor that interacts with the beta chain of the interleukin‑2 receptor. Science, 1994; 264: 965‑968
  Google Scholar
• 28. Han K.P., Zhu X., Liu B., Jeng E., Kong L., Yovandich J.L., Vyas V.V., Marcus W.D., Chavaillaz P.A., Romero C.A., Rhode P.R., Wong H.C.: IL‑15: IL‑15 receptor alpha superagonist complex: high‑level co‑expression in recombinant mammalian cells, purification and characterization. Cytokine, 2011; 56: 804‑810
  Google Scholar
• 29. Jakobisiak M., Golab J., Lasek W.: Interleukin 15 as a promising candidate for tumor immunotherapy. Cytokine Growth Factor Rev., 2011; 22: 99‑108
  Google Scholar
• 30. Jerez A., Clemente M.J., Makishima H., Koskela H., Leblanc F., Peng Ng K., Olson T., Przychodzen B., Afable M., Gomez‑Segui I., Guinta K., Durkin L., Hsi E.D., McGraw K., Zhang D. i wsp. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T‑cell large granular lymphocyte leukemia. Blood, 2012; 120: 3048‑3057
  Google Scholar
• 31. Jing W., Chen Y., Lu L., Hu X., Shao C., Zhang Y., Zhou X., Zhou Y., Wu L., Liu r., Fan K., Jin G.: Human umbilical cord blood‑derived mesenchymal stem cells producing IL15 eradicate established pancreatic tumor in syngeneic mice. Mol. Cancer Ther., 2014; 13: 2127‑2137
  Google Scholar
• 32. Jonuleit H., Wiedemann K., Müller G., Degwert J., Hoppe U., Knop J., Enk A.H.: 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; 158: 2610‑2615
  Google Scholar
• 33. Khawam K., Giron‑Michel J., Gu Y., Perier A., Giuliani M., Caignard A., Devocelle A., Ferrini S., Fabbi M., Charpentier B., Ludwig A., Chouaib S., Azzarone B., Eid P.: Human renal cancer cells express a novel membrane‑bound interleukin‑15 that induces, in response to the soluble interleukin‑15 receptor α chain, epithelial‑to‑mesenchymal transition. Cancer Res., 2009; 69: 1561‑1569
  Google Scholar
• 34. Koskela H.L., Eldfors S., Ellonen P., van Adrichem A.J., Kuusanmäki H., Andersson E.I., Lagström S., Clemente M.J., Olson T., Jalkanen S.E., Majumder M.M., Almusa H., Edgren H., Lepistö M., Mattila P. i wsp.: Somatic STAT3 mutations in large granular lymphocytic leukemia. N. Engl. J. Med., 2012; 366: 1905‑1913
  Google Scholar
• 35. Kuniyasu H., Ohmori H., Sasaki T., Sasahira T., Yoshida K., Kitadai Y., Fidler I.J.: Production of interleukin 15 by human colon cancer cells is associated with induction of mucosal hyperplasia, angiogenesis, and metastasis. Clin. Cancer Res., 2003; 9: 4802‑4810
  Google Scholar
• 36. Laprevotte E., Voisin G., Ysebaert L., Klein C., Daugrois C., Laurent G., Fournie J.J., Quillet‑Mary A.: Recombinant human IL‑15 trans‑presentation by B leukemic cells from chronic lymphocytic leukemia induces autologous NK cell proliferation leading to improved anti‑CD20 immunotherapy. J. Immunol., 2013; 191: 3634‑3640
  Google Scholar
• 37. Lin J.X., Migone T.S., Tsang M., Friedmann M., Weatherbee J.A., Zhou L., Yamauchi A., Bloom E.T., Mietz J., John S. i wsp.: 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; 2: 331‑339
  Google Scholar
• 38. Mishra A., Liu S., Sams G.H., Curphey D.P., Santhanam r., Rush L.J., Schaefer D., Falkenberg L.G., Sullivan L., Jaroncyk L., Yang X., Fisk H., Wu L.C., Hickey C., Chandler J.C. i wsp.: Aberrant overexpression of IL‑15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell, 2012; 22: 645‑655
  Google Scholar
• 39. Moga E., Canto E., Vidal S., Juarez C., Sierra J., Briones J.: Interleukin‑15 enhances rituximab‑dependent cytotoxicity against chronic lymphocytic leukemia cells and overcomes transforming growth factor beta‑mediated immunosuppression. Exp. Hematol., 2011; 39: 1064‑1071
  Google Scholar
• 40. Morris J.C., Janik J.E., White J.D., Fleisher T.A., Brown M., Tsudo M., Goldman C.K., Bryant B., Petrus M., Top L., Lee C.C., Gao W., Waldmann T.A.: Preclinical and phase I clinical trial of blockade of IL‑15 using Mikβ1 monoclonal antibody in T cell large granular lymphocyte leukemia. Proc. Natl. Acad. Sci. USA, 2006; 103: 401‑406
  Google Scholar
• 41. Mortier E., Bernard J., Plet A., Jacques Y.: Natural, proteolytic release of a soluble form of human IL‑15 receptor α‑chain that behaves as a specific, high affinity IL‑15 antagonist. J. Immunol., 2004; 173: 1681‑1688
  Google Scholar
• 42. Nishimura H., Fujimoto A., Tamura N., Yajima T., Wajjwalku W., Yoshikai Y.: A novel autoregulatory mechanism for transcriptional activation of the IL‑15 gene by a nonsecretable isoform of IL‑15 generated by alternative splicing. FASEB J., 2005; 19: 19‑28
  Google Scholar
• 43. Nishimura H., Yajima T., Naiki Y., Tsunobuchi H., Umemura M., Itano K., Matsuguchi T., Suzuki M., Ohashi P.S., Yoshikai Y.: Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo. J. Exp. Med., 2000; 191: 157‑170
  Google Scholar
• 44. Pagliari D., Cianci r., Frosali S., Landolfi r., Cammarota G., Newton E.E., Pandolfi F.: The role of IL‑15 in gastrointestinal diseases: a bridge between innate and adaptive immune response. Cytokine Growth Factor Rev., 2013; 24: 455‑466
  Google Scholar
• 45. Palena C., Schlom J.: Vaccines against human carcinomas: strategies to improve antitumor immune responses. J. Biomed. Biotechnol., 2010; 2010: 380697
  Google Scholar
• 46. Pandolfi F., Cianci r., Pagliari D., Casciano F., Bagala C., Astone A., Landolfi r., Barone C.: The immune response to tumors as a tool toward immunotherapy. Clin. Dev. Immunol., 2011; 2011: 894704
  Google Scholar
• 47. Perdreau H., Mortier E., Bouchaud G., Sole V., Boublik Y., Plet A., Jacques Y.: Different dynamics of IL‑15R activation following IL‑15 cis‑ or trans‑presentation. Eur. Cytokine Netw., 2010; 21: 297‑307
  Google Scholar
• 48. Sasahira T., Sasaki T., Kuniyasu H.: Interleukin‑15 and transforming growth factor alpha are associated with depletion of tumor‑associated macrophages in colon cancer. J. Exp. Clin. Cancer Res., 2005; 24: 69‑74
  Google Scholar
• 49. Schwartz r.N., Stover L., Dutcher J.: Managing toxicities of high‑dose interleukin‑2. Oncology, 2002; 16 (Suppl. 13): 11‑20
  Google Scholar
• 50. Steel J.C., Waldmann T.A., Morris J.C.: Interleukin‑15 biology and its therapeutic implications in cancer. Trends Pharmacol. Sci., 2012; 33: 35‑41
  Google Scholar
• 51. Tagaya Y., Burton J.D., Miyamoto Y., Waldmann T.A.: Identification of a novel receptor/signal transduction pathway for IL‑15/T in mast cells. EMBO J., 1996; 15: 4928‑4939
  Google Scholar
• 52. Tagaya Y., Kurys G., Thies T.A., Losi J.M., Azimi N., Hanover J.A., Bamford r.N., Waldmann T.A.: Generation of secretable and nonsecretable interleukin 15 isoforms through alternate usage of signal peptides. Proc. Natl. Acad. Sci. USA, 1997; 94: 14444‑14449
  Google Scholar
• 53. Tejman‑Yarden N., Zlotnik M., Lewis E., Etzion O., Chaimovitz C., Douvdevani A.: Renal cells express a functional interleukin‑15 receptor. Nephrol. Dial. Transplant., 2005; 20: 516‑523
  Google Scholar
• 54. Tinhofer I., Marschitz I., Henn T., Egle A., Greil r.: Expression of functional interleukin‑15 receptor and autocrine production of interleukin‑15 as mechanisms of tumor propagation in multiple myeloma. Blood, 2000; 95: 610‑618
  Google Scholar
• 55. Waldmann T.A., Conlon K.C., Stewart D.M., Worthy T.A., Janik J.E., Fleisher T.A., Albert P.S., Figg W.D., Spencer S.D., Raffeld M., Decker J.R., Goldman C.K., Bryant B.R., Petrus M.N., Creekmore S.P., Morris J.C.: Phase 1 trial of IL‑15 trans presentation blockade using humanized Mikβ1 mAb in patients with T‑cell large granular lymphocytic leukemia. Blood, 2013; 121: 476‑484
  Google Scholar
• 56. Wei C., Wang W., Pang W., Meng M., Jiang L., Xue S., Xie Y., Li r., Hou Z.: The CIK cells stimulated with combination of IL‑2 and IL‑15 provide an improved cytotoxic capacity against human lung adenocarcinoma. Tumour Biol., 2014; 35: 1997‑2007
  Google Scholar
• 57. Wei X., Orchardson M., Gracie J.A., Leung B.P., Gao B., Guan H., Niedbala W., Paterson G.K., McInnes I.B., Liew F.Y.: The Sushi domain of soluble IL‑15 receptor α is essential for binding IL‑15 and inhibiting inflammatory and allogenic responses in vitro and in vivo. J. Immunol., 2001; 167: 277‑282
  Google Scholar
• 58. Williams M.T., Yousafzai Y., Cox C., Blair A., Carmody r., Sai S., Chapman K.E., McAndrew r., Thomas A., Spence A., Gibson B., Graham G.J., Halsey C.: Interleukin‑15 enhances cellular proliferation and upregulates CNS homing molecules in pre‑B acute lymphoblastic leukemia. Blood, 2014; 123: 3116‑3127
  Google Scholar
• 59. Willimsky G., Blankenstein T.: Sporadic immunogenic tumours avoid destruction by inducing T‑cell tolerance. Nature, 2005; 437: 141‑146
  Google Scholar
• 60. Wu S., Fischer L., Gökbuget N., Schwartz S., Burmeister T., Notter M., Hoelzer D., Fuchs H., Blau I.W., Hofmann W.K., Thiel E.: Expression of interleukin 15 in primary adult acute lymphoblastic leukemia. Cancer, 2010; 116: 387‑392
  Google Scholar
• 61. Xu W., Jones M., Liu B., Zhu X., Johnson C.B., Edwards A.C., Kong L., Jeng E.K., Han K., Marcus W.D., Rubinstein M.P., Rhode P.R., Wong H.C.: Efficacy and mechanism‑of‑action of a novel superagonist interleukin‑15: interleukin‑15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res., 2013; 73: 3075‑3086
  Google Scholar
• 62. Yu P., Steel J.C., Zhang M., Morris J.C., Waldmann T.A.: Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin‑15 in a murine metastatic colon carcinoma model. Clin. Cancer Res., 2010; 16: 6019‑6028
  Google Scholar
• 63. Yu Y.L., Wei C.W., Chen Y.L., Chen M.H., Yiang G.T.: Immunotherapy of breast cancer by single delivery with rAAV2‑mediated interleukin‑15 expression. Int. J. Oncol., 2010; 36: 365‑370
  Google Scholar
• 64. Zambricki E., Shigeoka A., Kishimoto H., Sprent J., Burakoff S., Carpenter C., Milford E., McKay D.: Signaling T‑cell survival and death by IL‑2 and IL‑15. Am. J. Transplant., 2005; 5: 2623‑2631
  Google Scholar
• 65. Zhang M., Ju W., Yao Z., Yu P., Wei B.R., Simpson r.M., Waitz r., Fasso M., Allison J.P., Waldmann T.A.: Augmented IL‑15Rα expression by CD40 activation is critical in synergistic CD8 T cell‑mediated antitumor activity of anti‑CD40 antibody with IL‑15 in TRAMP‑C2 tumors in mice. J. Immunol., 2012; 188: 6156‑6164
  Google Scholar
• 66. Zhang M., Yao Z., Dubois S., Ju W., Müller J.R., Waldmann T.A.: Interleukin‑15 combined with an anti‑CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer. Proc. Natl. Acad. Sci. USA, 2009; 106: 7513‑7518
  Google Scholar
• 67. Żyzińska‑Granica B., Zegrodzka‑Stendel O., Niewieczerzał S., Trzaskowski B., Filipek S., Krzeczyński P., Winiarska M., Koziak K.: Hamowanie aktywności biologicznej interleukiny 15 ‑ nowe perspektywy. Post. Pol. Med. Farmacji, 2013; 3: 45‑55
  Google Scholar

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