title: Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer.
abstract: In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4(+)CD123(+)BDCA2(+) pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4(+) T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance.
authors.affiliation: Departments of Medical Oncology, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France. labidi@lyon.fnclcc.fr
authors.forename: Sana Intidhar
authors.initials: SI
authors.lastname: Labidi-Galy
authors.forename: Vanja
authors.initials: V
authors.lastname: Sisirak
authors.forename: Pierre
authors.initials: P
authors.lastname: Meeus
authors.forename: Michael
authors.initials: M
authors.lastname: Gobert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Agathe
authors.initials: A
authors.lastname: Bajard
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Combes
authors.forename: Julien
authors.initials: J
authors.lastname: Faget
authors.forename: François
authors.initials: F
authors.lastname: Mithieux
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cassignol
authors.forename: Olivier
authors.initials: O
authors.lastname: Tredan
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.forename: Christine
authors.initials: C
authors.lastname: Ménétrier-Caux
authors.forename: Christophe
authors.initials: C
authors.lastname: Caux
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bendriss-Vermare
mesh_terms: D015331:Cohort Studies; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D007959:Lymphocyte Culture Test, Mixed; D010051:Ovarian Neoplasms / Q000276:immunology*
chemical_list: D016207:Cytokines