title: Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells.
abstract: Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite its immunogenicity, effective antitumor responses are limited, due, in part, to the presence of forkhead box protein 3-positive (Foxp3(+)) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms that regulate the accumulation and the suppressive function of these Foxp3(+) Treg cells are poorly understood. Here, we found that the majority of Foxp3(+) Treg cells accumulating in the tumor microenvironment of EOCs belong to the subset of Foxp3(+) Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressive function of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoid dendritic cells (pDC). Accordingly, ICOS(+) Foxp3(+) Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS(+) Foxp3(+) Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS(+) Treg cell subset being a stronger predictor than total Foxp3(+) Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS(+) Foxp3(+) Treg cells, leading to tumor progression in ovarian cancer.
authors: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Curdin
authors: C
authors: Conrad
authors: Josh
authors: J
authors: Gregorio
authors: Yi-Hong
authors: YH
authors: Wang
authors: Tomoki
authors: T
authors: Ito
authors: Stephan
authors: S
authors: Meller
authors: Shino
authors: S
authors: Hanabuchi
authors: Sonya
authors: S
authors: Anderson
authors: Neely
authors: N
authors: Atkinson
authors: Pedro T
authors: PT
authors: Ramirez
authors: Yong-Jun
authors: YJ
authors: Liu
authors: Ralph
authors: R
authors: Freedman
authors: Michel
authors: M
authors: Gilliet
mesh_terms: D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D060889:Inducible T-Cell Co-Stimulator Protein / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D060889:Inducible T-Cell Co-Stimulator Protein