title: Plasmacytoid dendritic cells from human lung cancer draining lymph nodes induce Tc1 responses.
abstract: Dendritic cells (DC) resident in draining lymph nodes (LN) of patients with lung cancer are proposed to have a critical role in stimulating anti-tumor immunity. CpG oligodeoxynucleotides are undergoing clinical trials in patients with lung cancer and are likely to target plasmacytoid-DC. The present study, therefore, investigated the capacity of plasmacytoid-DC from human lung cancer draining LN to respond to CpG for activation of T cell responses relevant to anti-tumor immunity. The phenotype of DC was examined by flow cytometry, and cytokine production by cytometric bead array (CBA) and ELISA. Plasmacytoid-DC, purified by cell sorting, were immature but expressed the toll-like receptor, TLR9. Plasmacytoid-DC responded to the CpG oligodeoxynucleotide, CpG 2216, by production of the proinflammatory cytokines, IFN-alpha and IL-6. DC were cocultured with normal, allogeneic T cells, and cytokine production determined by CBA and immunophenotyping. CpG 2216 enhanced IFN-gamma production and induced intracellular production of IFN-gamma by CD8(+) and CD4(+), granzyme B by CD8(+), and IL-2 by CD4(+) T cells, respectively. Ligation of CD40 on plasmacytoid-DC combined with exposure to CpG 2216 also strongly enhanced IFN-gamma production. There was no significant difference between the responses of plasmacytoid-DC from patients with lung cancer and patients with benign carcinoid tumors with no pathologic LN involvement. These results indicate that plasmacytoid DC from the draining LN of patients with lung cancer effectively induce Tc1 immunity and could, therefore, represent a novel and attractive target for immunotherapeutic intervention.
authors.affiliation: Department of Asthma, Allergy and Respiratory Science, King's College, and Department of Thoracic Surgery, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. alex.faith@kcl.ac.uk
authors.forename: Alexander
authors.initials: A
authors.lastname: Faith
authors.forename: Emma
authors.initials: E
authors.lastname: Peek
authors.forename: Joanne
authors.initials: J
authors.lastname: McDonald
authors.forename: Zoe
authors.initials: Z
authors.lastname: Urry
authors.forename: David F
authors.initials: DF
authors.lastname: Richards
authors.forename: Carol
authors.initials: C
authors.lastname: Tan
authors.forename: George
authors.initials: G
authors.lastname: Santis
authors.forename: Catherine
authors.initials: C
authors.lastname: Hawrylowicz
mesh_terms: D023201:CD40 Ligand / Q000494:pharmacology; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology*; D022423:Myeloid Cells / Q000187:drug effects; D009841:Oligonucleotides / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; D007370:Interferon Type I; D009841:Oligonucleotides; D051217:Toll-Like Receptor 9; D023201:CD40 Ligand; D007371:Interferon-gamma