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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1566-1573.
Prepublished online as a Blood First Edition Paper on October 7, 2004; DOI 10.1182/blood-2004-04-1233.
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IMMUNOBIOLOGY
Fibromodulin as a novel tumor-associated antigen (TAA) in chronic lymphocytic leukemia (CLL), which allows expansion of specific CD8+ autologous T lymphocytes
Christine Mayr,
Dagmar Bund,
Martin Schlee,
Andreas Moosmann,
David M. Kofler,
Michael Hallek, and
Clemens-Martin Wendtner
From the Klinische Kooperationsgruppe (KKG) Gene Therapy, Munich, Germany, GSF-National Research Center for Environment and Health; Medical Clinic III, Klinikum Grosshadern Medical Center (KGMC), Ludwig-Maximilians-University, Munich; Medical Clinic I, University of Cologne, Cologne; Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, Munich, and the Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich, Germany.
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- (IFN-) upon recognition of the antigen demonstrated by IFN- 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.
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