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

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Date
2015-09
Authors
Holtzhausen, Alisha
Zhao, Fei
Evans, Kathy S
Tsutsui, Masahito
Orabona, Ciriana
Tyler, Douglas S
Hanks, Brent A
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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.
Type
Journal article
Subject
Animals
Antibodies, Monoclonal
Benzeneacetamides
CTLA-4 Antigen
Cell Communication
Cell Line, Tumor
Dendritic Cells
Disease Progression
Humans
Immune Tolerance
Immunotherapy
Indoleamine-Pyrrole 2,3,-Dioxygenase
Lymph Nodes
Melanoma
Membrane Proteins
Mice, Inbred Strains
Mice, Transgenic
Molecular Targeted Therapy
Neoplasm Transplantation
Proto-Oncogene Proteins
Pyridines
Signal Transduction
T-Lymphocytes, Regulatory
Wnt Proteins
Wnt-5a Protein
beta Catenin
Permalink
https://hdl.handle.net/10161/13296
Published Version (Please cite this version)
10.1158/2326-6066.CIR-14-0167
Publication Info
Holtzhausen, Alisha; Zhao, Fei; Evans, Kathy S; Tsutsui, Masahito; Orabona, Ciriana; Tyler, Douglas S; & Hanks, Brent A (2015). Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. Cancer Immunol Res, 3(9). pp. 1082-1095. 10.1158/2326-6066.CIR-14-0167. Retrieved from https://hdl.handle.net/10161/13296.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Hanks

Brent A. Hanks

Associate Professor of Medicine
We are interested in understanding the mechanisms that cancers have evolved to suppress the generation of tumor antigen-specific immune responses and how this knowledge can be exploited for the development of novel and more effective cancer immunotherapy strategies. This work involves the utilization of both autochthonous transgenic tumor model systems as well as clinical specimens to develop novel strategies to enhance the efficacy of immunotherapies while also developing predictive biomarkers
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