Abstract
Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8(+) T cells, eventually leading to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1). DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8(+) T cell priming in vitro; 2). exosomes require nature's adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-gamma (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen Presentation / immunology
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Antigens, Neoplasm
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / immunology*
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell-Free System / immunology
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Cells, Cultured
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Cytotoxicity, Immunologic
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Dendritic Cells / transplantation
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Endosomes / immunology*
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Endosomes / metabolism
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Endosomes / transplantation
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Epitopes, T-Lymphocyte / administration & dosage
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Epitopes, T-Lymphocyte / immunology
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HLA-A2 Antigen / administration & dosage
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HLA-A2 Antigen / immunology
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Histocompatibility Antigens Class I / administration & dosage
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Histocompatibility Antigens Class I / immunology*
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Humans
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Interphase / immunology
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Lymphocyte Activation / immunology
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MART-1 Antigen
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Mice
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Mice, Transgenic
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Neoplasm Proteins / administration & dosage
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Neoplasm Proteins / immunology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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Vaccines, Subunit / administration & dosage
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Vaccines, Subunit / immunology*
Substances
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Antigens, Neoplasm
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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HLA-A2 Antigen
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Histocompatibility Antigens Class I
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MART-1 Antigen
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MLANA protein, human
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Mlana protein, mouse
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Neoplasm Proteins
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Vaccines, Subunit