Retrovirus-mediated IL-7 expression in leukemic dendritic cells generated from primary acute myelogenous leukemias enhances their functional properties

Blood. 2003 Mar 15;101(6):2184-90. doi: 10.1182/blood-2002-02-0378. Epub 2002 Nov 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / immunology
  • Antigens, CD
  • B7-1 Antigen / analysis
  • CD83 Antigen
  • Cell Differentiation
  • Dendritic Cells / metabolism*
  • Dendritic Cells / pathology
  • Gene Expression*
  • Genes
  • Genetic Vectors
  • Humans
  • Immunoglobulins / analysis
  • In Situ Hybridization, Fluorescence
  • Interleukin-2 / analysis
  • Interleukin-7 / genetics*
  • Interleukin-7 / immunology
  • Interleukin-7 / metabolism
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Lymphocyte Culture Test, Mixed
  • Membrane Glycoproteins / analysis
  • Nerve Growth Factor / genetics
  • Recombinant Fusion Proteins
  • Retroviridae / genetics*
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Antigens, CD
  • B7-1 Antigen
  • Immunoglobulins
  • Interleukin-2
  • Interleukin-7
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • Nerve Growth Factor