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

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 15; pp. 4629 - 4640
• Main Authors: Le Mercier, Isabelle, Poujol, Dominique, Sanlaville, Amélien, Sisirak, Vanja, Gobert, Michael, Durand, Isabelle, Dubois, Bertrand, Treilleux, Isabelle, Marvel, Jacqueline, Vlach, Jaromir, Blay, Jean-Yves, Bendriss-Vermare, Nathalie, Caux, Christophe, Puisieux, Isabelle, Goutagny, Nadège
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2013
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cancer; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Female; Immunology; Immunotherapy; Life Sciences; Ligands; Lymphocyte Activation - immunology; Lymphocyte Culture Test, Mixed; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Membrane Glycoproteins - immunology; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pharmacology. Drug treatments; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 7 - metabolism; Tumors; Toll like receptor 7; Dendritic cell; Treatment; Antigen presenting cell; Ligand; Intratumoral administration; Tumor promotion; Plasmacytoid dendritic cell
• DOI: 10.1158/0008-5472.CAN-12-3058
• ISSN: 0008-5472; 1538-7445

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 in vivo and to activate CD4+ T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)–9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immune-subversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo 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. Cancer Res; 73(15); 4629–40. ©2013 AACR.