title: Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment.
abstract: 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.
authors.affiliation: Université de Lyon, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Mercier
authors.forename: Dominique
authors.initials: D
authors.lastname: Poujol
authors.forename: Amélien
authors.initials: A
authors.lastname: Sanlaville
authors.forename: Vanja
authors.initials: V
authors.lastname: Sisirak
authors.forename: Michael
authors.initials: M
authors.lastname: Gobert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dubois
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marvel
authors.forename: Jaromir
authors.initials: J
authors.lastname: Vlach
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bendriss-Vermare
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.forename: Isabelle
authors.initials: I
authors.lastname: Puisieux
authors.forename: Nadège
authors.initials: N
authors.lastname: Goutagny
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism
chemical_list: D008024:Ligands; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7