IL-4-transfected tumor cell vaccines activate tumor-infiltrating dendritic cells and promote type-1 immunity.
We previously demonstrated that IL-4 gene-transfected glioma cell vaccines induce effective therapeutic immunity in preclinical glioma models, and have initiated phase I trials of these vaccines in patients with malignant gliomas. To gain additional mechanistic insight into the efficacy of this approach, we have treated mice bearing the MCA205 (H-2(b)) or CMS-4 (H-2(d)) sarcomas. IL-12/23 p40(-/-) and IFN-gamma(-/-) mice, which were able to reject the initial inoculation of IL-4 expressing tumors, failed to mount a sustained systemic response against parental (nontransfected) tumor cells. Paracrine production of IL-4 in vaccine sites promoted the accumulation and maturation of IL-12p70-secreting tumor-infiltrating dendritic cells (TIDCs). Adoptive transfer of TIDCs isolated from vaccinated wild-type, but not IL-12/23 p40(-/-), mice were capable of promoting tumor-specific CTL responses in syngeneic recipient animals. Interestingly, both STAT4(-/-) and STAT6(-/-) mice failed to reject IL-4-transfected tumors in concert with the reduced capacity of TIDCs to produce IL-12p70 and to promote specific antitumor CTL reactivity. These results suggest that vaccines consisting of tumor cells engineered to produce the type 2 cytokine, IL-4, critically depend on type 1 immunity for their observed therapeutic efficacy.
Eguchi
Junichi
J
Department of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213, USA.
Kuwashima
Naruo
N
Hatano
Manabu
M
Nishimura
Fumihiko
F
Dusak
Jill E
JE
Storkus
Walter J
WJ
Okada
Hideho
H
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation*; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D053762:Interleukin-12 Subunit p40; D015847:Interleukin-4 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D021122:Protein Subunits / Q000502:physiology; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D012513:Sarcoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection
D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma