title: Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells.
abstract: Elevated levels of plasmacytoid dendritic cells (pDC) have been reported in breast cancer patients, but the significance remains undefined. Using three immunocompetent mouse models of breast cancer bone metastasis, we identified a key role for pDC in facilitating tumor growth through immunosuppression and aggressive osteolysis. Following infiltration of macrophages upon breast cancer dissemination, there was a steady increase in pDC within the bone, which resulted in a sustained Th2 response along with elevated levels of regulatory T cells and myeloid-derived suppressor cells. Subsequently, pDC and CD4(+) T cells, producing osteolytic cytokines, increased with tumor burden, causing severe bone damage. Microcomputed tomography and histology analyses of bone showed destruction of femur and tibia. The therapeutic significance of this finding was confirmed by depletion of pDC, which resulted in decreased tumor burden and bone loss by activating tumor-specific cytolytic CD8(+) T cells and decreasing suppressor cell populations. Thus, pDC depletion may offer a novel adjuvant strategy to therapeutically influence breast cancer bone metastasis.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Anandi
authors.initials: A
authors.lastname: Sawant
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hensel
authors.forename: Diptiman
authors.initials: D
authors.lastname: Chanda
authors.forename: Brittney A
authors.initials: BA
authors.lastname: Harris
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Akhil
authors.initials: A
authors.lastname: Maheshwari
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000556:secondary; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D010014:Osteolysis / Q000276:immunology; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D006131:Growth Inhibitors