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.
Type
Journal articleSubject
AnimalsAntibodies, 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
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https://hdl.handle.net/10161/13296Published Version (Please cite this version)
10.1158/2326-6066.CIR-14-0167Publication 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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Show full item recordScholars@Duke
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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