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.
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.
Wakita
Daiko
D
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Chamoto
Kenji
K
Zhang
Yue
Y
Narita
Yoshinori
Y
Noguchi
Daisuke
D
Ohnishi
Hideaki
H
Iguchi
Takeshi
T
Sakai
Tomoaki
T
Ikeda
Hiroaki
H
Nishimura
Takashi
T
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008081:Liposomes; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009374:Neoplasms, Experimental / Q000517:prevention & control / Q000628:therapy*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D007370:Interferon Type I; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin