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Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.

dc.contributor.author Evans, Kathy
dc.contributor.author Hanks, Brent A
dc.contributor.author Holtzhausen, A
dc.contributor.author Orabona, C
dc.contributor.author Tsutsui, M
dc.contributor.author Tyler, Douglas S
dc.contributor.author Zhao, Fei
dc.coverage.spatial United States
dc.date.accessioned 2017-01-01T18:35:24Z
dc.date.issued 2015-09
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/26041736
dc.identifier 2326-6066.CIR-14-0167
dc.identifier.uri http://hdl.handle.net/10161/13296
dc.description.abstract The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
dc.language eng
dc.relation.ispartof Cancer Immunol Res
dc.relation.isversionof 10.1158/2326-6066.CIR-14-0167
dc.subject Animals
dc.subject Antibodies, Monoclonal
dc.subject Benzeneacetamides
dc.subject CTLA-4 Antigen
dc.subject Cell Communication
dc.subject Cell Line, Tumor
dc.subject Dendritic Cells
dc.subject Disease Progression
dc.subject Humans
dc.subject Immune Tolerance
dc.subject Immunotherapy
dc.subject Indoleamine-Pyrrole 2,3,-Dioxygenase
dc.subject Lymph Nodes
dc.subject Melanoma
dc.subject Membrane Proteins
dc.subject Mice, Inbred Strains
dc.subject Mice, Transgenic
dc.subject Molecular Targeted Therapy
dc.subject Neoplasm Transplantation
dc.subject Proto-Oncogene Proteins
dc.subject Pyridines
dc.subject Signal Transduction
dc.subject T-Lymphocytes, Regulatory
dc.subject Wnt Proteins
dc.subject Wnt-5a Protein
dc.subject beta Catenin
dc.title Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/26041736
pubs.begin-page 1082
pubs.end-page 1095
pubs.issue 9
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group School of Medicine
pubs.publication-status Published
pubs.volume 3
dc.identifier.eissn 2326-6074


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