title: Melanoma-derived factors alter the maturation and activation of differentiated tissue-resident dendritic cells.
abstract: Dendritic cells (DCs) are key regulators of host immunity that are capable of inducing either immune tolerance or activation. In addition to their well-characterized role in shaping immune responses to foreign pathogens, DCs are also known to be critical for the induction and maintenance of anti-tumor immune responses. Therefore, it is important to understand how tumors influence the function of DCs and the quality of immune responses they elicit. Although the majority of studies in this field to date have utilized either immortalized DC lines or DC populations that have been generated under artificial conditions from hematopoietic precursors in vitro, we wished to investigate how tumors impact the function of already differentiated, tissue-resident DCs. Therefore, we used both an ex vivo and in vivo model system to assess the influence of melanoma-derived factors on DC maturation and activation. In ex vivo studies with freshly isolated splenic DCs, we demonstrate that the extent to which DC maturation and activation are altered by these factors correlates with melanoma tumorigenicity, and we identify partial roles for tumor-derived transforming growth factor (TGF)β1 and vascular endothelial growth factor (VEGF)-A in the altered functionality of DCs. In vivo studies using a lung metastasis model of melanoma also demonstrate tumorigenicity-dependent alterations to the function of lung-resident DCs, and skewed production of proinflammatory cytokines and chemokines by these tumor-altered cells is associated with recruitment of an immune infiltrate that may ultimately favor tumor immune escape and outgrowth.
authors.affiliation: Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, USA.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Hargadon
authors.affiliation: Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, USA.
authors.forename: Johnathan D
authors.initials: JD
authors.lastname: Bishop
authors.affiliation: Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Brandt
authors.affiliation: Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hand
authors.affiliation: Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, USA.
authors.forename: Yonathan T
authors.initials: YT
authors.lastname: Ararso
authors.affiliation: Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, USA.
authors.forename: Osric A
authors.initials: OA
authors.lastname: Forrest
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002452:Cell Count; D002454:Cell Differentiation; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D007155:Immunologic Factors / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018925:Chemokines; D007155:Immunologic Factors; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A