Abstract
Synthetic oligodeoxynucleotides containing CpG motifs (CpG DNA) can activate immunocompetent cells, which may possess antitumor activity. Previously, we found that when the cationic liposomes complexes formed with CpG DNA (CpG DNA lipoplex) were administered intranasally, they could prevent pulmonary metastasis in mice. However, the mechanisms underlying this process are unknown. In the present study, we show that natural killer (NK) cells play an important role in preventing pulmonary metastasis and peritoneal dissemination in a mouse model of metastatic disease. Further, in vitro, the NK cells obtained from mice treated with CpG DNA lipoplex showed higher cytotoxicity compared with untreated mice and in vivo, depletion of NK cells (achieved through injection of rabbit anti-asialo GM1 serum), abolished the inhibitory effect of CpG DNA lipoplex on pulmonary metastasis and peritoneal dissemination. In contrast, macrophage elimination did not disrupt the effects of the CpG DNA lipoplex. These results suggest that intranasal administration of CpG DNA lipoplex could prevent pulmonary metastasis and peritoneal dissemination by activating NK cells.
Similar content being viewed by others
Abbreviations
- CpG DNA:
-
Synthetic oligodeoxynucleotides containing CpG motifs
- CpG DNA lipoplex:
-
CpG DNA complexed with cationic liposome
- DOTMA:
-
N-[1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride
- i.p.:
-
Intraperitoneal
- NK cells:
-
Natural killer cells
- NT:
-
Not treated
- γ-C4:
-
γ-Carrageenan type IV
References
Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709–760
Krieg AM (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27(2):161–167
Nierkens S, den Brok MH, Roelofsen T et al (2009) Route of administration of the TLR9 agonist CpG critically determines the efficacy of cancer immunotherapy in mice. PLoS One 4(12):e8368
Kuramoto Y, Kawakami S, Zhou S et al (2008) Efficient peritoneal dissemination treatment obtained by an immunostimulatory phosphorothioate-type CpG DNA/cationic liposome complex in mice. J Control Release 126(3):274–280
Kuramoto Y, Kawakami S, Zhou S et al (2009) Mannosylated cationic liposomes/CpG DNA complex for the treatment of hepatic metastasis after intravenous administration in mice. J Pharm Sci 98(3):1193–1197
Ugwoke MI, Agu RU, Verbeke N et al (2005) Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. Adv Drug Deliv Rev 57(11):1640–1665
Almeida AJ, Alpar HO (1996) Nasal delivery of vaccines. J Drug Target 3:455–467
Zhou S, Kawakami S, Yamashita F et al (2010) Intranasal administration of CpG DNA lipoplex prevents pulmonary metastasis in mice. Cancer Lett 287(1):75–81
Schantz SP, Brown BW, Lira E et al (1987) Evidence for the role of natural immunity in the control of metastatic spread of head and neck cancer. Cancer Immunol Immunother 25:141–148
Vivier E, Tomasello E, Baratin M et al (2008) Functions of natural killer cells. Nat Immunol 9(5):503–510
Siveen KS, Kuttan G (2009) Role of macrophages in tumour progression. Immunol Lett 123(2):97–102
Moldoveanu Z, Love-Homan L, Huang WQ et al (1998) CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine 16(11–12):1216–1224
Pum PB, Bhat AA, Mohan T et al (2009) Intranasal administration of peptide antigens of HIV with mucosal adjuvant CpG ODN coentrapped in microparticles enhances the mucosal and systemic immune responses. Int Immunopharmacol 9(4):468–477
Corbctt TH, Griswold Jr, Robcrts BJ et al (1975) Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays with a note on carcinogen structure. Cancer Res 35(9):2434–2439
Hyoudou K, Nishikawa M, Umeyama Y et al (2004) Inhibition of metastatic tumor growth in mouse lung by repeated administration of polyethylene glycol-conjugated catalase: quantitative analysis with firefly luciferase-expressing melanoma cells. Clin Cancer Res 10(22):7685–7691
Kawakami S, Sato A, Nishikawa M et al (2000) Mannose receptor-mediated gene transfer into macrophages using novel mannosylated cationic liposomes. Gene Ther 7(4):292–299
Kuramoto Y, Nishikawa M, Hyoudou K et al (2006) Inhibition of peritoneal dissemination of tumor cells by single dosing of phosphodiester CpG oligonucleotide/cationic liposome complex. J Control Release 115(2):226–233
Wijagkanalan W, Kawakami S, Takenaga M et al (2008) Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats. J Control Release 125(2):121–130
Yoon TJ, Kim TJ, Lee H et al (2007) Anti-tumor metastatic activity of beta-glucan purified from mutated Saccharomyces cerevisiae. Int Immunopharmacol 8(1):36–42
Saiki I, Saito S, Fujita C et al (1998) Induction of tumoricidal macrophages and production of cytokines by synthetic muramyl dipeptide analogues. Vaccine 6:238–244
Yoon TJ, Yoo YC, Lee SW et al (2004) Anti-metastatic activity of Acanthopanax senticosus extract and its possible immunological mechanism of action. J Ethnopharmacol 93(2–3):247–253
Yoon TJ, Yoo YC, Kang TB et al (1998) Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity. Int J Immunopharmacol 20(4–5):163–172
Kitchens WH, Chase CM, Uehara S et al (2007) Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am J Transplant 7(12):2675–2682
Gregoire C, Chasson L, Luci C et al (2007) The trafficking of natural killer cells. Immunol Rev 220:169–182
Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47:187–376
Bahjat KS, Prell RA, Allen HE et al (2007) Activation of immature hepatic NK cells as immunotherapy for liver metastatic disease. J Immunol 179(11):7376–7384
Sivori S, Falco M, Della Chiesa M et al (2004) CpG and double-stranded RNA trigger human NK cells by toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc Natl Acad Sci USA 101(27):10116–10121
Paget C, Bialecki E, Fontaine J et al (2009) Role of invariant NK T lymphocytes in immune responses to CpG oligodeoxynucleotides. J Immunol 182(4):1846–1853
Lysaght J, Jarnicki AG, Mills KH (2007) Reciprocal effects of Th1 and Treg cell inducing pathogen-associated immunomodulatory molecules on anti-tumor immunity. Cancer Immunol Immunother 56(9):1367–1379
Shindo H, Ogura T, Masuno T et al (1985) Induction of activated macrophages by intraperitoneal injection of mitomycin C in mice. Cancer Immunol Immunother 20(2):145–15025
Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217
Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796(1):11–18
Zeisberger SM, Odermatt B, Marty C et al (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95:272–281
Suzuki K, Suda T, Naito T et al (2005) Impaired toll-like receptor 9 expression in alveolar macrophages with no sensitivity to CpG DNA. Am J Respir Crit Care Med 171(7):707–713
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research (A) (23240072) and by a fellowship grant from the Japan Society for the Promotion of Sciences (23·2743).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhou, S., Kawakami, S., Higuchi, Y. et al. The involvement of NK cell activation following intranasal administration of CpG DNA lipoplex in the prevention of pulmonary metastasis and peritoneal dissemination in mice. Clin Exp Metastasis 29, 63–70 (2012). https://doi.org/10.1007/s10585-011-9429-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10585-011-9429-1