title: Intranodal injection of semimature monocyte-derived dendritic cells induces T helper type 1 responses to protein neoantigen.
abstract: Dendritic cells (DCs) represent the most potent antigen-presenting cells of the immune system capable of initiating primary immune responses to neoantigens. Here we characterize the primary CD4 T-cell immune response to protein keyhole limpet hemocyanin (KLH) in 5 metastatic melanoma patients undergoing a tumor peptide-based dendritic cell vaccination trial. Monocyte-derived dendritic cells displaying a semimature phenotype, as defined by surface markers, were loaded ex vivo with antigen and injected intranodally at weekly intervals for 4 weeks. All patients developed a strong and long-lasting delayed-type hypersensitivity reactivity to KLH, which correlated with the induction of KLH-dependent proliferation of CD4 T cells in vitro. Secondary in vitro stimulation with KLH showed significant increase in interferon-gamma and interleukin-2 (IL-2) but not IL-4, IL-5, nor IL-10 secretion by bulk T cells. On the single-cell level, most TH1 cells among in vitro-generated KLH-specific T-cell lines confirmed the preferential induction of a KLH-specific type 1 T helper immune response. Furthermore, the induction of KLH-specific antibodies of the IgG2 subtype may reflect the induction of a type 1 cytokine profile in vivo after vaccination. Our results indicate that intranodal vaccination with semimature DCs can prime strong, long-lasting CD4 T-cell responses with a TH1-type cytokine profile in cancer patients.
authors.affiliation: Department of Dermatology, University of Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.forename: Martin
authors.initials: M
authors.lastname: Kleinhans
authors.forename: Erica
authors.initials: E
authors.lastname: Lantelme
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Günter
authors.initials: G
authors.lastname: Burg
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
mesh_terms: D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000276:immunology; D018929:Cell Culture Techniques / Q000379:methods; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007272:Injections, Intralymphatic; D008213:Lymphocyte Activation; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D009000:Monocytes / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin