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

Publication ,  Journal Article
Holtzhausen, A; Zhao, F; Evans, KS; Tsutsui, M; Orabona, C; Tyler, DS; Hanks, BA
Published in: Cancer Immunol Res
September 2015

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.

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Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

September 2015

Volume

3

Issue

9

Start / End Page

1082 / 1095

Location

United States

Related Subject Headings

  • beta Catenin
  • Wnt-5a Protein
  • Wnt Proteins
  • T-Lymphocytes, Regulatory
  • Signal Transduction
  • Pyridines
  • Proto-Oncogene Proteins
  • Neoplasm Transplantation
  • Molecular Targeted Therapy
  • Mice, Transgenic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Holtzhausen, A., Zhao, F., Evans, K. S., Tsutsui, M., Orabona, C., Tyler, D. S., & Hanks, B. 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), 1082–1095. https://doi.org/10.1158/2326-6066.CIR-14-0167
Holtzhausen, Alisha, Fei Zhao, Kathy S. Evans, Masahito Tsutsui, Ciriana Orabona, Douglas S. Tyler, and Brent A. Hanks. “Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.Cancer Immunol Res 3, no. 9 (September 2015): 1082–95. https://doi.org/10.1158/2326-6066.CIR-14-0167.
Holtzhausen A, Zhao F, Evans KS, Tsutsui M, Orabona C, Tyler DS, et al. Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. Cancer Immunol Res. 2015 Sep;3(9):1082–95.
Holtzhausen, Alisha, et al. “Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.Cancer Immunol Res, vol. 3, no. 9, Sept. 2015, pp. 1082–95. Pubmed, doi:10.1158/2326-6066.CIR-14-0167.
Holtzhausen A, Zhao F, Evans KS, Tsutsui M, Orabona C, Tyler DS, Hanks BA. Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. Cancer Immunol Res. 2015 Sep;3(9):1082–1095.

Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

September 2015

Volume

3

Issue

9

Start / End Page

1082 / 1095

Location

United States

Related Subject Headings

  • beta Catenin
  • Wnt-5a Protein
  • Wnt Proteins
  • T-Lymphocytes, Regulatory
  • Signal Transduction
  • Pyridines
  • Proto-Oncogene Proteins
  • Neoplasm Transplantation
  • Molecular Targeted Therapy
  • Mice, Transgenic