Abstract
Fibromodulin (FMOD) was shown to be highly overexpressed in chronic lymphocytic leukemia (CLL) cells compared with normal B lymphocytes by gene expression profiling. Therefore FMOD might serve as potential tumor-associated antigen (TAA) in CLL, enabling expansion of FMOD-specific T cells. In CLL samples derived from 16 different patients, high expression of FMOD by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was detectable in contrast to normal B lymphocytes. We used unpulsed native CLL cells and CD40 ligand (CD40L)-stimulated CLL cells as antigen-presenting cells (APCs) to expand autologous T cells from 13 patients. The number of T cells during 4 weeks of in vitro culture increased 2- to 3.5-fold and the number of T cells recognizing FMOD peptides bound to HLA-A2 dimers increased 10-fold. The expanded T cells also were able to secrete interferon-gamma (IFN-gamma) upon recognition of the antigen demonstrated by IFN-gamma ELISPOT assays. T cells not only recognized HLA-A2-binding FMOD peptides presented by transporter-associated with antigen-processing (TAP)-deficient T2 cells, but also FMOD overexpressing autologous CLL cells in an HLA-A2-restricted manner. In summary, FMOD was shown for the first time to be naturally processed and presented as TAA in primary CLL cells, enabling the expansion of autologous tumor-specific T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Antigen Presentation
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigen-Presenting Cells / pathology
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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Antigens, Neoplasm / metabolism
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CD40 Ligand / pharmacology
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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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Cell Line, Transformed
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Cell Line, Tumor
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Dimerization
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Enzyme-Linked Immunosorbent Assay
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Epitopes, T-Lymphocyte / immunology*
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Epitopes, T-Lymphocyte / metabolism
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Extracellular Matrix Proteins / biosynthesis
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / immunology*
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Extracellular Matrix Proteins / metabolism
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Female
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Fibromodulin
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HLA-A2 Antigen / immunology
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HLA-A2 Antigen / metabolism
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymphocyte Activation / immunology*
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Male
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Middle Aged
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Proteoglycans / biosynthesis
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Proteoglycans / genetics
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Proteoglycans / immunology*
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Proteoglycans / metabolism
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RNA, Messenger / biosynthesis
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Staining and Labeling
Substances
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Antigens, Neoplasm
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Epitopes, T-Lymphocyte
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Extracellular Matrix Proteins
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FMOD protein, human
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HLA-A2 Antigen
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Peptide Fragments
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Proteoglycans
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RNA, Messenger
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Fibromodulin
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CD40 Ligand