title: Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer.
abstract: Within the ovarian cancer microenvironment, there are several mechanisms that suppress the actions of antitumor immune effectors. Delineating the complex immune microenvironment is an important goal toward developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell (DC)-associated B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, programmed death receptor-1 (PD-1), is also expressed on myeloid cells, complicating interpretations of how B7-H1 regulates DC function in the tumor. In this study, we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1(+) B7-H1(+) DCs have a classical DC phenotype (i.e., CD11c(+)CD11b(+)CD8(-)), but are immature, suppressive, and respond poorly to danger signals. Accumulation of PD-1(+)B7-H1(+) DCs in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell-associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DCs suppressed NF-κB activation, release of immune regulatory cytokines, and upregulation of costimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector Ag-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1(+)B7-H1(+) DCs in mediating immune suppression in ovarian cancer.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: James
authors.initials: J
authors.lastname: Krempski
authors.forename: Lavakumar
authors.initials: L
authors.lastname: Karyampudi
authors.forename: Marshall D
authors.initials: MD
authors.lastname: Behrens
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Erskine
authors.forename: Lynn
authors.initials: L
authors.lastname: Hartmann
authors.forename: Haidong
authors.initials: H
authors.lastname: Dong
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D060890:B7-H1 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D005260:Female; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D047368:Tumor Burden / Q000276:immunology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor