Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Cancer Vaccines / administration & dosage
-
Cancer Vaccines / genetics
-
Cancer Vaccines / immunology*
-
Cell Line, Tumor
-
Cell Movement / genetics
-
Cell Movement / immunology*
-
DNA-Binding Proteins / physiology
-
Dendritic Cells / metabolism*
-
Dendritic Cells / pathology
-
Dendritic Cells / transplantation*
-
Female
-
Fibrosarcoma / genetics
-
Fibrosarcoma / immunology*
-
Fibrosarcoma / pathology
-
Graft Rejection / genetics
-
Graft Rejection / immunology
-
Immunity, Cellular / genetics
-
Interferon-gamma / biosynthesis
-
Interferon-gamma / physiology
-
Interleukin-12 / administration & dosage
-
Interleukin-12 / genetics
-
Interleukin-12 / physiology
-
Interleukin-12 Subunit p40
-
Interleukin-4 / administration & dosage
-
Interleukin-4 / biosynthesis
-
Interleukin-4 / genetics*
-
Killer Cells, Natural / immunology
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Nude
-
Protein Subunits / physiology
-
STAT4 Transcription Factor
-
STAT6 Transcription Factor
-
Sarcoma, Experimental / genetics
-
Sarcoma, Experimental / immunology*
-
Sarcoma, Experimental / pathology
-
T-Lymphocyte Subsets / immunology
-
Trans-Activators / physiology
-
Transfection*
Substances
-
Cancer Vaccines
-
DNA-Binding Proteins
-
Interleukin-12 Subunit p40
-
Protein Subunits
-
STAT4 Transcription Factor
-
STAT6 Transcription Factor
-
Stat4 protein, mouse
-
Stat6 protein, mouse
-
Trans-Activators
-
Interleukin-12
-
Interleukin-4
-
Interferon-gamma