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

Satthaporn, Sukchai and Aloysius, Mark M. and Robins, Richard A. and Verma, Chandan and Chuthapisith, Suebwong and Mckechnie, Alasdair J. and El-Sheemy, Mohamad and Vassanasiri, Wichai and Valerio, David and Clark, David and Jibril, Jibril A. and Eremin, Oleg (2008) Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha. BMC Immunology, 9 (1). p. 32. ISSN 1471-2172

Full content URL: http://dx.doi.org/10.1186/1471-2172-9-32

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Item Type:Article
Item Status:Live Archive

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-α+IFN-α) or 3 CCM (GM-CSF+IL-4+TNF-α) 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-α. Maximal immunophenotypic recovery and functional reactivation of DCs is seen in the presence of IFN-α. However, 4 CCM containing IFN-α generated-PBDCs, do not produce and secrete IL-12p70 in vitro.

Keywords:Cancer immunotherapy
Subjects:B Subjects allied to Medicine > B100 Anatomy, Physiology and Pathology
Divisions:College of Science > School of Life Sciences
ID Code:9798
Deposited On:10 Jun 2013 09:07

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