Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy.
The idiotype protein, secreted by myeloma plasma cells, is a tumor-specific but weak antigen. Idiotype-based immunotherapy has been explored in myeloma patients with disappointing results. It is conceivable that myeloma cells contain a multitude of tumor antigens that can more effectively stimulate antitumor T cells. To explore the possibility of using whole myeloma cells as a source of tumor antigens for immunotherapy, the current study was undertaken to generate and examine the function of myeloma-specific cytotoxic T lymphocytes (CTLs) by using dendritic cells (DCs) pulsed with myeloma cell lysates as stimulating cells. After repeated stimulation, specific CTL lines, containing CD4(+) and CD8(+) T cells, were generated from myeloma patients. Our results show that these T cells not only recognized and lysed autologous myeloma protein-pulsed DCs, they also killed autologous primary myeloma cells. Occasionally, CTLs responded to autologous idiotype-pulsed DCs and to allogeneic primary myeloma cells. No cytolytic activity, however, was detected against autologous lymphocytes including B cells, suggesting that the T cells acted specifically against myeloma cells. Cytotoxicity against target cells was major histocompatibility complex class 1 and, to a lesser extent, class 2 restricted and was dependent mainly on the perforin-mediated pathway. CTLs secreted predominantly interferon-gamma and tumor necrosis factor-alpha on antigenic stimulation, indicating a type 1 T-cell subset. These findings represent the first demonstration that tumor cell lysate-primed CTLs kill only myeloma cells, not autologous lymphocytes. This provides a rationale for myeloma cell-based immunotherapy in multiple myeloma.
Wen
Yue-Jin
YJ
Myeloma and Transplantation Research Center, University of Arkansas for Medical Science, Little Rock 72205, USA.
Min
Rui
R
Tricot
Guido
G
Barlogie
Bart
B
Yi
Qing
Q
D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D018929:Cell Culture Techniques; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D054353:Perforin; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D016207:Cytokines; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin