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

• Main Authors: El-Sheemy Mohamad, Mckechnie Alasdair J, Chuthapisith Suebwong, Verma Chandan, Robins Richard A, Aloysius Mark M, Satthaporn Sukchai, Vassanasiri Wichai, Valerio David, Clark David, Jibril Jibril A, Eremin Oleg
• Format: Article
• Language: English
• Published: BMC 2008-06-01
• Series: BMC Immunology
• Online Access: http://www.biomedcentral.com/1471-2172/9/32

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>Peripheral blood DCs (PBDCs) and lymph node DCs (LNDCs) generated <it>in vitro </it>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) <it>in vitro </it>(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).</p> <p>Conclusion</p> <p>Dysfunctional and anergic PBDCs and LNDCs from patients with operable breast cancer can be optimally reversed by <it>ex vivo </it>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 <it>in vitro</it>.</p>