β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin a metabolism in dendritic cells

Yuan Hong, Indumathi Manoharan, Amol Suryawanshi, Tanmay Majumdar, Melinda L. Angus-Hill, Pandelakis A. Koni, Balaji Manicassamy, Andrew L. Mellor, David H. Munn, Santhakumar Manicassamy

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Tumors actively suppress antitumor immunity, creating formidable barriers to successful cancer immunotherapy. The molecular mechanisms underlying tumor-induced immune tolerance are largely unknown. In the present study, we show that dendritic cells (DC) in the tumor microenvironment acquire the ability to metabolize vitamin A to produce retinoic acid (RA), which drives regulatory T-cell responses and immune tolerance. Tolerogenic responses were dependent on induction of vitamin A-metabolizing enzymes via the β-catenin/T-cell factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of β-catenin in mice markedly reduced regulatory T-cell responses and delayed melanoma growth. Pharmacologic inhibition of either vitamin A- metabolizing enzymes or the β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and regulatory T-cell responses. Hence, β-catenin/TCF4 signaling induces local regulatory DC and regulatory T-cell phenotypes via the RA pathway, identifying this pathway as an important target for anticancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)656-665
Number of pages10
JournalCancer Research
Volume75
Issue number4
DOIs
StatePublished - Feb 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hong, Y., Manoharan, I., Suryawanshi, A., Majumdar, T., Angus-Hill, M. L., Koni, P. A., Manicassamy, B., Mellor, A. L., Munn, D. H., & Manicassamy, S. (2015). β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin a metabolism in dendritic cells. Cancer Research, 75(4), 656-665. https://doi.org/10.1158/0008-5472.CAN-14-2377