title: Immunoregulation of Dendritic Cell Subsets by Inhibitory Receptors in Urothelial Cancer.
abstract: Blockade of inhibitory receptors (IRs) overexpressed by T cells can activate antitumor immune responses, resulting in the most promising therapeutic approaches, particularly in bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-present antigens to T cells, dendritic cells (DCs) are an immune cell population that plays a central role in the generation of effective antitumor T-cell responses. While IR function and expression have been investigated in T cells, very few data are available for DCs. Therefore, we analyzed whether DCs express IRs that can decrease their functions. To this end, we investigated several IRs (PD-1, CTLA-4, BTLA, TIM-3, and CD160) in circulating CD1c+DCs, CD141+DCs, and plasmacytoid DCs from healthy donors and patients with urothelial cancer (UCa). Different DC subsets expressed BTLA and TIM-3 but not other IRs. More importantly, BTLA and TIM-3 were significantly upregulated in DCs from blood of UCa patients. Locally, bladder tumor-infiltrating DCs also overexpressed BTLA and TIM-3 compared to DCs from paired nontumoral tissue. Finally, in vitro functional experiments showed that ligand-mediated engagement of BTLA and TIM-3 receptors significantly reduced the secretion of effector cytokines by DC subpopulations. Our findings demonstrate that UCa induces local and systemic overexpression of BTLA and TIM-3 by DCs that may result in their functional inhibition, highlighting these receptors as potential targets for UCa treatment.
  
  
  
  We investigated the expression and function of a panel of inhibitory receptors in dendritic cells (DCs), an immune cell subpopulation critical in initiation of protective immune responses, among patients with urothelial carcinoma. We found high expression of BTLA and TIM-3 by blood and tumor DCs, which could potentially mediate decreased DC function. The results suggest that BTLA and TIM-3 might be new targets for urothelial carcinoma treatment.
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Mathieu F
authors.initials: MF
authors.lastname: Chevalier
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Perrine
authors.initials: P
authors.lastname: Bohner
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Claire
authors.initials: C
authors.lastname: Pieraerts
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lhermitte
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gourmaud
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Nobile
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotman
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Cesson
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Virginie
authors.initials: V
authors.lastname: Martin
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Legris
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Dartiguenave
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Dalila
authors.initials: D
authors.lastname: Gharbi
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: De Leval
authors.affiliation: Department of Oncology and Ludwig Cancer Research, University of Lausanne, Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Nardelli-Haefliger
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Jichlinski
authors.affiliation: Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Electronic address: laurent.derre@chuv.ch.
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000032:analysis*; D006801:Humans; D010641:Phenotype; D011971:Receptors, Immunologic / Q000032:analysis*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000473:pathology; D019459:Urothelium / Q000276:immunology* / Q000473:pathology
chemical_list: C482586:BTLA protein, human; D014408:Biomarkers, Tumor; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D011971:Receptors, Immunologic
keywords: BTLA; Dendritic cells; Inhibitory receptors; TIM-3; Urothelial cancer