title: Effect of oxygen levels on the physiology of dendritic cells: implications for adoptive cell therapy.
abstract: Dendritic cell (DC)-based adoptive tumor immunotherapy approaches have shown promising results, but the incidence of tumor regression is low and there is an evident call for identifying culture conditions that produce DCs with a more potent Th1 potential. Routinely, DCs are differentiated in CO(2) incubators under atmospheric oxygen conditions (21% O(2)), which differ from physiological oxygen levels of only 3-5% in tissue, where most DCs reside. We investigated whether differentiation and maturation of DCs under physiological oxygen levels could produce more potent T-cell stimulatory DCs for use in adoptive immunotherapy. We found that immature DCs differentiated under physiological oxygen levels showed a small but significant reduction in their endocytic capacity. The different oxygen levels did not influence their stimuli-induced upregulation of cluster of differentiation 54 (CD54), CD40, CD83, CD86, C-C chemokine receptor type 7 (CCR7), C-X-C chemokine receptor type 4 (CXCR4) and human leukocyte antigen (HLA)-DR or the secretion of interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-10 in response to lipopolysaccharide (LPS) or a cytokine cocktail. However, DCs differentiated under physiological oxygen level secreted higher levels of IL-12(p70) after exposure to LPS or CD40 ligand. Immature DCs differentiated at physiological oxygen levels caused increased T-cell proliferation, but no differences were observed for mature DCs with regard to T-cell activation. In conclusion, we show that although DCs generated under atmospheric or physiological oxygen conditions are mostly similar in function and phenotype, DCs differentiated under physiological oxygen secrete larger amounts of IL-12(p70). This result could have implications for the use of ex vivo-generated DCs for clinical studies, since DCs differentiated at physiological oxygen could induce increased Th1 responses in vivo.
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
authors.forename: Diahnn
authors.initials: D
authors.lastname: Futalan
authors.forename: Chien-Tze
authors.initials: CT
authors.lastname: Huang
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D004705:Endocytosis / Q000276:immunology; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D019013:CD40 Antigens; D007136:Immunoglobulins; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D018664:Interleukin-12; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010100:Oxygen; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen