title: Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
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.
authors.affiliation: Department of Pharmacology and Cell Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Alisha
authors.initials: A
authors.lastname: Holtzhausen
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Evans
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tsutsui
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy.
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.affiliation: Department of Surgery, Division of Surgical Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
authors.affiliation: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina. brent.hanks@duke.edu.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Hanks
mesh_terms: D000217:Acyltransferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D044482:Benzeneacetamides / Q000494:pharmacology / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D018450:Disease Progression; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051153:Wnt Proteins / Q000502:physiology*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: C579131:2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide; D000911:Antibodies, Monoclonal; D044482:Benzeneacetamides; D060908:CTLA-4 Antigen; C495270:CTNNB1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000217:Acyltransferases; C491188:PORCN protein, human