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.
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| 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 approximately 50% of tumor-bearing mice became completely cured. Tumor eradication correlated with the generation of OVA/H-2K(b)-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.
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| Authors | Daiko Wakita, Kenji Chamoto, Yue Zhang, Yoshinori Narita, Daisuke Noguchi, Hideaki Ohnishi, Takeshi Iguchi, Tomoaki Sakai, Hiroaki Ikeda, Takashi Nishimura |
| Journal | International immunology (Int Immunol) Vol. 18 Issue 3 Pg. 425-34 (Mar 2006) ISSN: 0953-8178 [Print] England |
| PMID | 16415100 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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