Abstract
Both the underlying molecular mechanisms and the kinetics of TCR repertoire selection following vaccination against tumor Ags in humans have remained largely unexplored. To gain insight into these questions, we performed a functional and structural longitudinal analysis of the TCR of circulating CD8(+) T cells specific for the HLA-A2-restricted immunodominant epitope from the melanocyte differentiation Ag Melan-A in a melanoma patient who developed a vigorous and sustained Ag-specific T cell response following vaccination with the corresponding synthetic peptide. We observed an increase in functional avidity of Ag recognition and in tumor reactivity in the postimmune Melan-A-specific populations as compared with the preimmune blood sample. Improved Ag recognition correlated with an increase in the t(1/2) of peptide/MHC interaction with the TCR as assessed by kinetic analysis of A2/Melan-A peptide multimer staining decay. Ex vivo analysis of the clonal composition of Melan-A-specific CD8(+) T cells at different time points during vaccination revealed that the response was the result of asynchronous expansion of several distinct T cell clones. Some of these T cell clones were also identified at a metastatic tumor site. Collectively, these data show that tumor peptide-driven immune stimulation leads to the selection of high-avidity T cell clones of increased tumor reactivity that independently evolve within oligoclonal populations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Antigens, Neoplasm / administration & dosage
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Antigens, Neoplasm / immunology*
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Antigens, Neoplasm / metabolism
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Base Sequence
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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Cancer Vaccines / administration & dosage
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Cancer Vaccines / immunology*
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Cell Adhesion / immunology
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Cell Differentiation / immunology
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Clone Cells
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Complementarity Determining Regions / biosynthesis
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Complementarity Determining Regions / genetics
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DNA Primers / genetics
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Epitopes, T-Lymphocyte / metabolism
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Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
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Genes, T-Cell Receptor beta
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HLA-A2 Antigen / biosynthesis
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Humans
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Immunoglobulin Variable Region / biosynthesis
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Immunoglobulin Variable Region / genetics
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Immunophenotyping
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Longitudinal Studies
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MART-1 Antigen
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Melanoma / immunology*
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Melanoma / pathology
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Molecular Sequence Data
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Neoplasm Proteins / administration & dosage
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Neoplasm Proteins / immunology*
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Neoplasm Proteins / metabolism
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology*
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Peptide Fragments / metabolism
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Sequence Analysis, DNA
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocyte Subsets / pathology
Substances
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Antigens, Neoplasm
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Cancer Vaccines
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Complementarity Determining Regions
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DNA Primers
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Epitopes, T-Lymphocyte
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HLA-A2 Antigen
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Immunoglobulin Variable Region
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MART-1 Antigen
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MLANA protein, human
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Neoplasm Proteins
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Peptide Fragments