Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha

BMC Immunol. 2008 Jun 27;9:32. doi: 10.1186/1471-2172-9-32.

Abstract

Background: Dendritic cells (DCs) play a crucial role in initiating effective cell-mediated immune responses, but are dysfunctional and anergic in breast cancer. Reversal of this dysfunction and establishment of optimal DC function is a key prerequisite for the induction of effective anti-cancer immune responses.

Results: Peripheral blood DCs (PBDCs) and lymph node DCs (LNDCs) generated in vitro from adherent cultures of peripheral blood monocytes (PBMs) and lymph node monocytes (LNMs), respectively, using the 4 cytokine conditioned medium (CCM) (GM-CSF+IL-4+TNF-alpha+IFN-alpha) or 3 CCM (GM-CSF+IL-4+TNF-alpha) demonstrated a significantly higher degree of recovery and functional capacity in a mixed lymphocyte DC reaction (MLDCR, p < 0.001), expressed significantly higher levels of HLA-DR, CD86, compared with 2 CCM (GM-CSF+IL-4) or medium alone generated DCs from PBMs and LNMs (p < 0.001). The PBDCs generated with 3 CCM or 4 CCM showed a significantly (p < 0.001) enhanced macropinocytotic capability (dextran particles) and induced increased production and secretion of interleukin-12p40 (IL-12p40) in vitro (p < 0.001), compared with PBDCs generated from monocytes using 2 CCM or medium alone. Lipopolysaccharide (LPS) stimulation of PBDCs generated with 4 CCM demonstrated enhanced secretion of IL-6 but not IL-12p70, compared with control DCs unstimulated with LPS (p < 0.001).

Conclusion: Dysfunctional and anergic PBDCs and LNDCs from patients with operable breast cancer can be optimally reversed by ex vivo culturing of precursor adherent monocytes using a 4 CCM containing IFN-alpha. Maximal immunophenotypic recovery and functional reactivation of DCs is seen in the presence of IFN-alpha. However, 4 CCM containing IFN-alpha generated-PBDCs, do not produce and secrete IL-12p70 in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-2 Antigen / immunology
  • B7-2 Antigen / metabolism*
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / metabolism
  • Cells, Cultured
  • Culture Media, Conditioned
  • Cytokines / immunology
  • Cytokines / metabolism*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Humans
  • Immunophenotyping
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism*
  • Lectins, C-Type / metabolism
  • Lymphocytes / immunology
  • Mannose-Binding Lectins / metabolism
  • Pinocytosis
  • Receptors, Cell Surface / metabolism

Substances

  • B7-2 Antigen
  • Culture Media, Conditioned
  • Cytokines
  • Interferon-alpha
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • mannose receptor