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International Immunology Advance Access originally published online on January 13, 2006
International Immunology 2006 18(3):425-434; 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

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

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

Correspondence to: T. Nishimura; E-mail: tak24{at}igm.hokudai.ac.jp

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-ß mAbs but not with anti-IFN-{alpha} or anti-IFN-ß 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}/ß, 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.

Transmitting editor: M. Miyasaka


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