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International Immunology Advance Access published online on January 13, 2006
International Immunology, doi:10.1093/intimm/dxh381
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received November 9, 2005
Accepted December 9, 2005

Article

An indispensable role of type-1 IFNs for inducing CTL-mediated complete eradication of established tumor tissue by CpG-liposome co-encapsulated with model tumor antigen

Daiko Wakita 1 *, Kenji Chamoto 1 *, Yue Zhang 1, Yoshinori Narita 1, Daisuke Noguchi 1, Hideaki Ohnishi 1, Takeshi Iguchi 1, Tomoaki Sakai 1, Hiroaki Ikeda 1, and Takashi Nishimura 1 *

1 Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan

* To whom correspondence should be addressed.
Takashi Nishimura, E-mail: tak24{at}igm.hokudai.ac.jp


  Abstract

We have evaluated the capacity of a novel, nanoparticle-based tumor vaccine to eradicate established tumors in mice. C57BL/6 mice were intradermally (i.d.) inoculated with ovalbumin (OVA)-expressing EG-7 tumor cells. When the tumor size reached 7-8 mm, the tumor-bearing mice were i.d. injected near the tumor-draining lymph node (DLN) with liposomes encapsulated with unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotides (CpG-ODN) (CpG-liposomes) co-encapsulated with OVA. This vaccination protocol markedly prevented the growth of the established tumor mass and ~50% of tumor-bearing mice became completely cured. Tumor eradication correlated with the generation of OVA/H-2Kb-tetramer+ CTLs in the tumor DLN and at the tumor site with specific cytotoxicity toward EG-7 cells. Interestingly, tetramer+ CTLs failed to be induced in lymph node-deficient Aly/Aly mice. Thus, tetramer+ CTLs appeared to be generated in the tumor DLN and subsequently migrated into the tumor site. In vivo antibody blocking experiments revealed that CD8+ T cells, but not CD4+ T, NK or NKT cells, were the major effector cells mediating tumor eradication. CTL induction was also inhibited when vaccinated tumor-bearing mice were treated with both anti-IFN-{alpha} and anti-IFN-{beta} mAbs but not with anti-IFN-{alpha} or anti-IFN-{beta} mAb alone. Neither IFN-{gamma}-/- nor IL-12-/- mice showed impaired induction of tetramer+ CTLs. Thus, these findings revealed that CpG-ODN-induced IFN-{alpha}/{beta}, but not IL-12 or IFN-{gamma}, is critical for the generation of tumor-specific CTLs in response to vaccination. These results highlight the potential utility of CpG-liposomes co-encapsulated with protein tumor antigens as therapeutic vaccines in cancer patients.

Keywords: CpG-oligonucleotide; IFN-alpha/beta; liposome; tumor-specific CTL; tumor vaccination therapy.

*These authors contributed equally to this study.


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