Abstract
We have previously shown that the fusion of GM-CSF and IL-21 (GIFT-21) possesses a potent immune stimulatory effect on myeloid cells. In this study, we define the effect of GIFT-21 on naive murine monocytes (GIFT-21 dendritic cells [DCs]), which express increased levels of Gr-1, CD45R, MHC class I, CD80, CD86, and CXCR4 and suppress CD11c and MHC class II. Compared with conventional dendritic cells, GIFT-21 DCs produced substantially more CCL2, IL-6, TNF-α, and IFN-α and induced significantly greater production of IFN-γ by CD8(+) T cells in MHC class I-restricted Ag presentation assays. B16 melanoma and D2F2 Neu breast cancer growth was inhibited in mice treated with Ag-naive GIFT-21 DCs. This effect was lost in CD8(-/-) and CCR2(-/-) mice and when mice were treated with β(2)-microglobulin-deficient GIFT-21 DCs, indicating that GIFT-21 DCs migrated to and sampled from the tumors to present tumor Ags to CCL2 recruited CD8(+) T cells via MHC class I. We propose that autologous GIFT-21 DCs may serve as a cell therapy platform for the treatment of cancer.
MeSH terms
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Adoptive Transfer
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Animals
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Antigen Presentation / drug effects
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Antigen Presentation / genetics
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Antigen Presentation / immunology
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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CD8-Positive T-Lymphocytes / immunology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Movement / immunology
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Cytokines / genetics
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Cytokines / immunology
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Dendritic Cells / immunology*
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Dendritic Cells / transplantation
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Female
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
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Immunity, Cellular / drug effects*
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Immunity, Cellular / genetics
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Immunity, Cellular / immunology
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Interleukins / immunology*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / immunology*
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Mammary Neoplasms, Experimental / therapy
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Melanoma / genetics
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Melanoma / immunology*
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Melanoma / therapy
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Recombinant Fusion Proteins / pharmacology*
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Transplantation, Autologous
Substances
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Antigens, Differentiation
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Antigens, Neoplasm
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Cytokines
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Interleukins
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Recombinant Fusion Proteins
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Granulocyte-Macrophage Colony-Stimulating Factor
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interleukin-21