Fibromodulin as a novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (CLL), which allows expansion of specific CD8+ autologous T lymphocytes.
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.
Klinische Kooperationsgruppe Gene Therapy, Munich, Germany.
Christine
C
Mayr
Dagmar
D
Bund
Martin
M
Schlee
Andreas
A
Moosmann
David M
DM
Kofler
Michael
M
Hallek
Clemens-Martin
CM
Wendtner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000071235:Fibromodulin; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D013194:Staining and Labeling
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D011509:Proteoglycans; D012333:RNA, Messenger; D000071235:Fibromodulin; D023201:CD40 Ligand