Impaired IFN-α Production by Plasmacytoid Dendritic Cells Favors Regulatory T-cell Expansion That May Contribute to Breast Cancer Progression

Abstract

Infiltration and dysfunction of immune cells have been documented in many types of cancers. We previously reported that plasmacytoid dendritic cells (pDC) within primary breast tumors correlate with an unfavorable prognosis for patients. The role of pDC in cancer remains unclear but they have been shown to mediate immune tolerance in other pathophysiologic contexts. We postulated that pDC may interfere with antitumor immune response and favor tolerance in breast cancer. The present study was designed to decipher the mechanistic basis for the deleterious impact of pDC on the clinical outcome. Using fresh human breast tumor biopsies (N ¼ 60 patients), we observed through multiparametric flow cytometry increased tumor-associated (TA) pDC (TApDC) rates in aggressive breast tumors, i.e., those with high mitotic index and the so-called triple-negative breast tumors (TNBT). Furthermore, TApDC expressed a partially activated phenotype and produced very low amounts of IFN-a following toll-like receptor activation in vitro compared with patients' blood pDC. Within breast tumors, TApDC colocalized and strongly correlated with TA regulatory T cells (TATreg), especially in TNBT. Of most importance, the selective suppression of IFN-a production endowed TApDC with the unique capacity to sustain FoxP3 þ Treg expansion, a capacity that was reverted by the addition of exogenous IFN-a. These findings indicate that IFNa-deficient TApDC accumulating in aggressive tumors are involved in the expansion of TATreg in vivo, contributing to tumor immune tolerance and poor clinical outcome. Thus, targeting pDC to restore their IFN-a production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer. Cancer Res; 72(20); 5188-97. Ó2012 AACR.

Research in practice: The impact of interferon‐α therapy on immune tolerance

“…The results of these experiments are in accordance with other studies showing that treatment with IFN-α in patients with malignant melanoma or renal cell carcinoma lead to a reduction of the number and function of Tregs, whereas reduced levels of IFN-α in tumor patients seem to provoke a reduction of Tregs worsening the patients prognosis and outcome [17][18][19]. On the other hand, several studies prove that the risk of autoimmunity increases following treatment with IFN-α.…”

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

“…By contrast, the capacity of CCR-derived pDCs to produce IFNa upon CpG stimulation was partially defective (Fig. 9f), as largely documented in patients with other carcinoma types 34,40,41 . Significantly, number and function (for example, cytokine production) of the slanDC contingent was maintained even in advanced disease stages (Fig.…”

Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression

“…This is in accordance with previous reports showing higher proportions of T effector cells upon treatment with CpG (28). The TLR7 agonist imiquimod increased the T effector cell to Treg ratio in human squamous cell cancer but did not alter the proportion of antigen-specific T effector and Treg cells in the lymph node in a murine antitumor vaccine model (29,30 (15,(32)(33)(34). We describe here the blockade of Treg migration as a novel mechanism of action in the process of innate immune activation by ligands for PRR.…”