title: Induction of leukemia-specific CD8+ cytotoxic T cells with autologous myeloid leukemic cells maturated with a fiber-modified adenovirus encoding TNF-alpha.
abstract: Acute myeloid leukemia (AML) cells can be differentiated into dendritic cells (DCs) using appropriate combinations of cytokines but generation of autologous antileukemic cytotoxic T cells using leukemic DCs remains difficult. Transduction by adenoviral vectors has been reported to induce efficient maturation of monocyte-derived DCs but AML cells are generally resistant to adenoviral gene transfer. In this study we tested the effects of adenoviral TNF-alpha gene transfer on maturation of AML cells using the fiber-modified AdTNF.F(pK7) adenovirus. All samples expressed high and sustained levels of TNF-alpha following transduction. AdTNF.F(pK7) induced significantly greater maturation of AML cells into antigen-presenting cells (APC) than did recombinant TNF-alpha or control adenoviral vector. Maturation of leukemic cells into APCs was mediated at least partially via a PI3K/mTOR pathway, as the inhibitors LY294002, wortmannin, and rapamycin inhibited the maturation effect induced by the AdTNF.F(pK7) adenovirus. In addition, CD8+ T cells expanded with AdTNF.F(pK7)-transduced AML cells showed greater expansion and specific CD8+ CTL activity against autologous AML cells than T cells expanded by other means. Thus, fiber-modified adenoviral vectors encoding TNF-alpha are able to maturate AML cells into APCs with high efficacy and reproducibility, providing a useful tool to generate efficiently specific CD8+ CTLs against leukemic disease.
authors.affiliation: Unité INSERM 524, Institut de Recherche sur le Cancer de Lille, 59037 Lille, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Saudemont
authors.forename: Selim
authors.initials: S
authors.lastname: Corm
authors.forename: Thomas
authors.initials: T
authors.lastname: Wickham
authors.forename: Dominique
authors.initials: D
authors.lastname: Hetuin
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
mesh_terms: D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics*; D000938:Antigen-Presenting Cells / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics; D002454:Cell Differentiation; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D036022:Capsid Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; C018315:hexon capsid protein, Adenovirus; C546842:MTOR protein, human