title: PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB.
abstract: The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida.
authors.forename: Lavakumar
authors.initials: L
authors.lastname: Karyampudi
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Purushottam
authors.initials: P
authors.lastname: Lamichhane
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: James
authors.initials: J
authors.lastname: Krempski
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Marshall D
authors.initials: MD
authors.lastname: Behrens
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Doris M
authors.initials: DM
authors.lastname: Vargas
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.affiliation: Department of Gynecologic Surgery Mayo Clinic, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jo Marie T
authors.initials: JM
authors.lastname: Janco
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Haidong
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Hedin
authors.affiliation: Human Cell Therapy Lab, Mayo Clinic, Rochester, Minnesota.
authors.forename: Allan B
authors.initials: AB
authors.lastname: Dietz
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota. knutson.keith@mayo.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D061026:Programmed Cell Death 1 Receptor