Retrovirus-mediated IL-7 expression in leukemic dendritic cells generated from primary acute myelogenous leukemias enhances their functional properties.
Myeloid lineage-derived dendritic cells (DCs) are considered the professional antigen-presenting cell type responsible for eliciting T-cell-mediated immune responses. Acute myelogenous leukemia (AML) is a disease in which tumor antigens are expressed by the malignant clone that also has the potential to differentiate into DC-like cells (leukemic DCs) with antigen-presenting capacity. This study investigated whether the constitutive expression of the cytokine interleukin-7 (IL-7) in primary AML cells during their differentiation toward leukemic DCs results in superior antigen-presenting cells. A bicistronic retroviral vector encoding the IL-7 cytokine and the surface immunoselectable low-affinity nerve growth factor receptor (LNGFr) gene was constructed and used for transduction experiments. A serum-free system was used to transduce and differentiate leukemic cells toward leukemic DCs. The study included 8 patients with AML. The transduction efficiency with the cytokine vector varied among patients, ranging from 5% to 30% as judged by LNGFr expression. The leukemic origin of the transduced cells was confirmed in a patient with a chromosomal translocation t(9:11) by fluorescence in situ hybridization analysis. Cytokine modified-cells consistently secreted IL-7 (mean, 415 pg +/- 190/10(6) cells/48 hours; n = 5). We demonstrate that IL-7-transduced cells are included in the differentiated leukemic DC subset, and, as shown in a particular case, that about half of the mature CD80(+) and CD83(+) populations coexpress the LNGFr transgene. In addition, IL-7-modified leukemic cells induce stronger allo-T-cell stimulation and higher amounts of IL-2 production in T cells compared with control groups. Finally, cytokine-transduced leukemic DCs can effectively prime and generate cytotoxic T lymphocytes against autologous leukemic blasts.
Bello-Fernández
Concha
C
Institute of Immunology, Vienna International Research Cooperation Center (VIRCC), University of Vienna, Vienna, Austria. concha@kabsi.at
Stasakova
Jana
J
Renner
Alexander
A
Carballido-Perrig
Nicole
N
Koening
Margit
M
Waclavicek
Martina
M
Madjic
Otto
O
Oehler
Leopold
L
Haas
Oskar
O
Carballido
José M
JM
Buschle
Michael
M
Knapp
Walter
W
D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D018122:B7-1 Antigen / Q000032:analysis; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D005796:Genes; D005822:Genetic Vectors; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D017404:In Situ Hybridization, Fluorescence; D007376:Interleukin-2 / Q000032:analysis; D015851:Interleukin-7 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000032:analysis; D020932:Nerve Growth Factor / Q000235:genetics; D011993:Recombinant Fusion Proteins; D012190:Retroviridae / Q000235:genetics*; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D000097802:CD83 Antigen
D015703:Antigens, CD; D018122:B7-1 Antigen; D007136:Immunoglobulins; D007376:Interleukin-2; D015851:Interleukin-7; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D000097802:CD83 Antigen