Abstract
To develop a tumor vaccine directly targeting tumor antigen to dendritic cells in situ, we engineered human mesothelin (MSLN) into an antibody specific for mouse DEC-205, a receptor for antigen presentation. We then characterized both T cell and humoral responses to human MSLN and compared immunizing efficacy of DEC-205-targeted MSLN to nontargeted protein after a single-dose immunization. Targeting human MSLN to DEC-205 receptor induced stronger CD4(+) T-cell responses compared to high doses of mesothelin protein. Approximately 0.5% CD4(+) T cells were primed to produce IFN-gamma, tumor necrosis factor-alpha, and IL-2 via intracellular cytokine staining, and the T cells also could proliferate rapidly. The immune response exhibited breadth because the primed CD4(+) T cells responded to at least three epitopes in the H-2(b) background. Targeting MSLN protein to DEC-205 receptor also resulted in cross-presentation to CD8(+) T cells. Antibody responses against human MSLN were also detected in serum from primed mice by ELISA assays. In summary, targeting of MSLN to DEC-205 improves the induction of CD4(+) and CD8(+) T-cell immunity accompanied by an antibody response. DEC-205-targeting could be valuable for enhancing immunity to MSLN in cancers where this nonmutated protein is expressed.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antibody Formation / immunology
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Antigens, CD / drug effects
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Antigens, CD / immunology*
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Antigens, Neoplasm / immunology*
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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Colony-Stimulating Factors / immunology
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Colony-Stimulating Factors / pharmacology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Enzyme-Linked Immunosorbent Assay
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Epitopes / immunology
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GPI-Linked Proteins
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Humans
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Immunization / methods
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Interferon gamma Receptor
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Lectins, C-Type / drug effects
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Lectins, C-Type / immunology*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / pharmacology
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Mesothelin
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Minor Histocompatibility Antigens
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Receptors, Cell Surface / drug effects
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Receptors, Cell Surface / immunology*
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Receptors, Interferon / deficiency
Substances
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Antigens, CD
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Antigens, Neoplasm
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Colony-Stimulating Factors
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DEC-205 receptor
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Epitopes
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GPI-Linked Proteins
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Lectins, C-Type
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MSLN protein, human
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Membrane Glycoproteins
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Minor Histocompatibility Antigens
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Msln protein, mouse
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Receptors, Cell Surface
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Receptors, Interferon
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Mesothelin