Interleukin-15 (IL-15) is known to stimulate the proliferation of CD8+ T-cells and natural killer cells, and also to help to maintain memory CD8+ T cells, suggesting that it may be of value in cytokine treatment of bladder cancer. In this experiment, we tested the efficiency of intravesical liposomal IL-15 gene delivery and its antitumor effect in a mouse orthotopic bladder cancer model. We established an orthotopic bladder cancer model by implanting 5×105 MBT-2 cells into female C3H/HeN mice through the urethra. The mice received repeated intravesical gene delivery injected with liposome-mediated plasmids (5 μg) transurethrally. On day 23, the bladder weights in the group receiving medium alone, the beta-galactosidase gene delivery control group, and the IL-15 gene therapy group were 196±36 mg, 201±35 mg, and 96±29 mg, respectively (p<0.05), demonstrating the antitumor effect of intravesical IL-15 gene therapy in this model. In the bladders treated with IL-15 gene plasmid instillation, histological analysis revealed that many inflammatory cells were induced around the tumors. Immunohistochemical analysis confirmed that there was predominant infiltration of CD8+ T cells around the tumor nest. After the intravesical IL-15 gene therapy, the growth of rechallenged subcutaneous MBT-2 cells in surviving mice was inhibited again via tumor-specific cytotoxic T lymphocytes, although newly implanted FM3A cells in the same mice were not rejected. The present findings indicate that IL-15 gene therapy may be a promising new adjuvant therapy for bladder cancer.
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References
1.
AlexandroffA.B., JacksonA.M., O'DonnellM.A., JamesK.1999. BCG immunotherapy of bladder cancer: 20 years on. Lancet, 353:1689–1694.
2.
AndersonW.F.1998. Human gene therapy. Nature, 392:25–30.
3.
ArmitageR.J., MacduffB.M., EisenmanJ.et al.1995. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J. Immunol., 154:483–490.
4.
BamfordR.N., GrantA.J., BurtonJ.D.et al.1994. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc. Natl. Acad. Sci. USA, 91:4940–4944.
5.
BeckerT.C., WherryE.J., BooneD.et al.2002. Interleukin 15 is required for proliferative renewal of virus specific memory CD8 T cells. J. Exp. Med., 195:1541–1548.
6.
BöhleA., BrandauS.2003. Immune mechanisms in bacillus Calmette-Guérin immunotherapy for superficial bladder cancer. J. Urol., 170:964–969.
7.
BrandauS., SuttmannH.2007. Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement. Biomed. Pharmacother., 61:299–305.
8.
CarsonW.E., GiriJ.G., LindemannM.J.et al.1995. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J. Exp. Med., 180:1395–1403.
9.
ChapmanP.B., HoughtonA.N.1993. Non-antibody immunotherapy of cancer. Curr. Opin. Immunol., 5:726–731.
10.
ColucciF., CaligiuriM.A., Di SantoJ.P.2003. What does it take to make a natural killer?Nat. Rev. Immunol., 3:413–425.
11.
ConnorJ., BannerjiR., SaitoS.et al.1993. Regression of bladder tumors in mice treated with interleukin-2 gene modified tumor cells. J. Exp. Med., 177:1127–1134.
12.
EvansR., FullerJ.A., ChristiansonG.et al.1997. IL-15 mediates anti-tumor effects after cyclophosphamide injection of tumor-bearing mice and enhances adoptive immunotherapy: the potential role of NK cell subpopulations. Cell. Immunol., 179:66–73.
13.
FehnigerT.A., SuzukiK., PonnappanA.et al.2001. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J. Exp. Med., 193:219–231.
14.
FidlerI.J.1990. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res., 50:6130–6138.
15.
GameroA.M., UsseryD., ReintgenD.S.et al.1995. Interleukin-15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism. Cancer Res., 55:4988–4994.
16.
GiriJ.G., AhdiehM., EisenmanJ.et al.1994. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J., 13:2822–2830.
17.
GrabsteinK.H., EisenmanJ., ShanebeckK.et al.1994. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science, 264:965–968.
18.
HazamaS., NomaT., WangF.et al.1999. Tumour cells engineered to secrete interleukin-15 augment anti-tumour immune responses in vivo. Br. J. Cancer, 80:1420–1426.
19.
HoriguchiY., LarchianW.A., KaplinskyR.et al.2000. Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model. Gene Ther., 7:844–851.
20.
HoriguchiY., KikuchiE., OzuC.et al.2008. Establishment of orthotopic mouse superficial bladder tumor model for studies on intravesical treatments. Human Cell, 21:57–63.
21.
HorinagaM., HarschK.M., FukuyamaR.et al.2005. Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model. Urology, 66:461–466.
22.
JaffeeE.M., DranoffG., CohenL.K.et al.1993. High efficiency gene transfer into primary human tumor explants without cell selection. Cancer Res., 53:2221–2226.
23.
KennedyM.K., GlaccumM., BrownS.N.et al.2000. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin-15 deficient mice. J. Exp. Med., 191:771–780.
24.
KikuchiE., MenendezS., OzuC.et al.2007. Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors. Clin. Cancer Res., 13:4511–4518.
25.
LeeM.J., ChoS.S., YouJ.R.et al.2002. Intraperitoneal gene delivery mediated by a novel cationic liposome in a peritoneal disseminated ovarian cancer model. Gene Ther., 9:859–866.
26.
LewkoW.M., SmithT.L., BowmanD.J.et al.1995. Interleukin-15 and the growth of tumor derived activated T-cells. Cancer Biother., 10:13–20.
27.
MillerD.G., AdamM.A., MillerA.D.1990. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol. Cell. Biol., 10:4239–4942.
28.
MoralesA., EidingerD., BruceA.W.1976. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116:180–183.
29.
MoriA., SukoM., KaminumaO.et al.1996. IL-15 promotes cytokine production of human T helper cells. J. Immunol., 156:2400–2405.
30.
MungerW., DeJoyS.Q., JeyaseelanR.Sr.et al.1995. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2. Cell. Immunol., 165:289–293.
31.
NishimuraH., YajimaT., NaikiY.et al.2000. Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo. J. Exp. Med., 191:157–170.
32.
RatliffT.L.2000. Role of animal models in understanding intravesical therapy with bacille Calmette-Guérin. Clin. Infect. Dis., 31,suppl 3:106–108.
33.
RatliffT.L., GillenD., CatalonaW.J.1987. Requirement of a thymus dependent immune response for BCG-mediated antitumor activity. J. Urol., 137:155–158.
34.
RatliffT.L., RitcheyJ.K., YuanJ.J.et al.1993. T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J. Urol., 150:1018–1023.
35.
SchlunsK.S., WilliamsK., MaA.et al.2002. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol., 168:4827–4831.
36.
SiemensD.R., CristS., AustinJ.C.et al.2003. Comparison of viral vectors: gene transfer efficiency and tissue specificity in a bladder cancer model. J. Urol., 170:979–984.
37.
SuzukiK., NakazatoH., MatsuiH.et al.2001. NK cell-mediated anti-tumor immune response to human prostate cancer cell, PC-3, immunogene therapy using a highly secretable form of interleukin-15 gene transfer. J. Leukoc. Biol., 69:531–537.
38.
SylvesterR.J.2011. Bacillus Calmette-Guérin treatment of non-muscle invasive bladder cancer. Int. J. Urol., 18:113–120.
39.
TakeuchiE., YanagawaH., YanoS.et al.1996. Induction by interleukin-15 of human killer cell activity against lung cancer cell lines and its regulatory mechanisms. Jpn. J. Cancer Res., 87:1251–1258.
40.
TasakiK., YoshidaY., MiyauchiM.et al.2000. Transduction of murine colon carcinoma cells with interleukin-15 gene induces antitumor effects in immunocompetent and immunocompromised hosts. Cancer Gene Ther., 7:255–261.
41.
ToriF.M., LumB.L.1984. The biology and treatment of superficial bladder cancer. J. Clin. Oncol., 2:505–531.
42.
WaldmannT.A.2006. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol., 6:595–601.
43.
WaldmannT.A., DuboisS., TagayaY.2001. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity, 14:105–110.
44.
WoodM., PerrotteP., OnishiE.et al.1999. Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse. Cancer Gene Ther., 6:367–372.
45.
YajimaT., NishimuraH., IshimitsuR.et al.2002. Overexpression of IL-15 in vivo increases antigen-driven memory CD8+ T cells following a microbe exposure. J. Immunol., 168:1198–1203.
46.
ZhangX., SunS., HwangI.et al.1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity, 8:591–599.
