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

J Immunother. 2007 Jan;30(1):75-82. doi: 10.1097/01.cji.0000211316.15278.6e.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Dendritic Cells / immunology*
  • Female
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / immunology
  • Interleukin-12 / biosynthesis
  • Interleukin-12 / immunology*
  • Lipopolysaccharides / immunology
  • Male
  • Melanoma / immunology*
  • Melanoma / therapy*
  • Middle Aged
  • Th1 Cells / immunology*

Substances

  • Antigens, Neoplasm
  • Lipopolysaccharides
  • Interleukin-12
  • Interferon-gamma