Data from Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment

Abstract

<div>Abstract<p>Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens <i>in vivo</i> and to activate CD4<sup>+</sup> T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)–9 ligands <i>in vitro</i> while preserving unaltered response to TLR7 ligands (TLR7L). <i>In vivo</i> pDC depletion delayed tumor growth, showing that TApDC provide an immune-subversive environment, most likely through Treg activation, thus favoring tumor progression. However, <i>in vivo</i> intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. <i>Cancer Res; 73(15); 4629–40. ©2013 AACR</i>.</p></div>