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 = 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-α 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-α production endowed TApDC with the unique capacity to sustain FoxP3(+) Treg expansion, a capacity that was reverted by the addition of exogenous IFN-α. These findings indicate that IFN-α-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-α production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer.

Highlights

  • Functional alteration of tumor-associated dendritic cells (TADC) that play a critical role in antitumor immunity, as well as mobilization of immunosuppressive regulatory T cells (Treg) that shut down immune responses, have been associated with tumor tolerance [1]

  • We previously showed that plasmacytoid DC and Treg infiltrating breast tumors correlate with an adverse clinical outcome [3, 4], suggesting that both plasmacytoid dendritic cells (pDC) and Treg are involved in breast cancer progression

  • We previously reported that infiltration of primary breast tumors by pDC identified as CD123þ cells by immunohistochemistry (IHC) correlates with poor prognosis, with a median follow-up of 5 years [4]

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Summary

Introduction

Functional alteration of tumor-associated dendritic cells (TADC) that play a critical role in antitumor immunity, as well as mobilization of immunosuppressive regulatory T cells (Treg) that shut down immune responses, have been associated with tumor tolerance [1]. Authors' Affiliations: 1Universite de Lyon; 2Universite Lyon 1, ISPB; 3INSERM U1052, Centre de Recherche en Cancerologie de Lyon; 4CNRS UMR5286, Centre de Recherche en Cancerologie de Lyon; 5LabEx DEVweCAN; 6Centre Leon Berard, Lyon, France; and 7Institut Universitaire de France, Paris, France. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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