Infiltration and dysfunction of immune cells has been observed in numerous cancers. After finding that plasmacytoid dendritic cells (pDC) in primary breast tumors correlated with unfavorable prognosis, Sisirak and colleagues from INSERM (Institut National de la Santé et de la Recherche Médicale) and Centre Léon Bérard in Lyon, France, hypothesized that these cells may interfere with antitumor immune response and favor immune tolerance.
In studies to ascertain the potential mechanisms by which plasmacytoid dendritic cells may mediate poorer outcome, the investigators found that tumor-associated plasmacytoid dendritic cells were increased in aggressive breast tumors—ie, those with a high mitotic index and triple-negative tumors. The tumor-associated plasmacytoid dendritic cells expressed a partially activated phenotype and produced very small amounts of interferon (IFN)-α after toll-like receptor activation in vitro compared with patient blood plasmacytoid dendritic cells.
Within the breast tumors, the tumor-associated plasmacytoid dendritic cells co-localized with and were strongly correlated with tumor-associated regulatory T cells (Treg), especially in triple-negative tumors. When IFN-α production was selectively suppressed, the tumor-associated plasmacytoid dendritic cells exhibited a unique capacity to sustain FOXP3-positive Treg expansion, with this activity being reversed when exogenous IFN-α was added.
As stated by the investigators, “These findings indicate that IFN-α–deficient [tumor-associated] pDC accumulating in aggressive tumors are involved in the expansion of tumor-associated Treg in vivo, contributing to tumor immune tolerance and poor clinical outcome. Thus, targeting pDC to restore their IFN-α production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer.” ■
Sisirak V, et al: Cancer Res 72:5188-5197, 2012.