title: Polarized type-1 dendritic cells (DC1) producing high levels of IL-12 family members rescue patient TH1-type antimelanoma CD4+ T cell responses in vitro.
abstract: Deficiencies in TH1-type immunity in patients with cancer may facilitate tumor progression and limit the effectiveness of current immunotherapy approaches. We hypothesized that Type-1 polarized dendritic cells (DC1) might be able to recondition patient antitumor CD4+ T cell responses toward the TH1-type in vitro. Although DC1 have been previously demonstrated to prime TH1 responses from naive CD4+ T cells, their impact on antigen-experienced TH responses remains unknown. We confirmed our own earlier observations that patient CD4+ T cell reactivity against melanoma-associated antigens (MAA) was weaker and less Type-1-polarized than their corresponding antiviral responses. Stimulation of patient CD4 T cells with peptide-pulsed DC1 (producing multiple IL-12 family member cytokines, including IL-12p70, IL-23, and IL-27) promoted robust TH1-type, epitope-specific T cell responses. Addition of exogenous IL-12 family member cytokines alone, or in combination, to nonpolarized DC was insufficient to equate to the benefits associated with DC1-based stimulation; however, IL-27 and IL-12p70 blockade neutralized the ability of DC1 cells to enhance TH1-type antitumor immunity in vitro. Notably, DC1-based stimulation seemed capable of "revitalizing" defective TH1-type responses within the CD45RO+ subset of antigen-experienced CD4+ T cells in melanoma patients. In addition to promoting elevated levels of IFN-gamma from responder CD4+ T cells, DC1-based stimulation also led to increased levels of IL-12Rbeta2 and t-bet expression by TH cells. These results suggest that preexisting CD4+ T cell immunity to cancer is not relegated to Type-1 insufficiency and may be corrected via the application of DC1-based vaccination protocols.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, PA 1513, USA. wesaak@upmc.edu
authors.forename: Amy
authors.initials: A
authors.lastname: Wesa
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D008070:Lipopolysaccharides; D018664:Interleukin-12; D007371:Interferon-gamma