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

33 Citations (Scopus)

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

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Catenins
Regulatory T-Lymphocytes
Vitamins
Dendritic Cells
Vitamin A
Immune Tolerance
Tretinoin
Immunotherapy
Neoplasms
TCF Transcription Factors
Tumor Microenvironment
Enzymes
Growth
Immunity
Melanoma
Phenotype

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin a metabolism in dendritic cells. / Hong, Yuan; Manoharan, Indumathi; Suryawanshi, Amol; Majumdar, Tanmay; Angus-Hill, Melinda L.; Koni, Pandelakis A.; Manicassamy, Balaji; Mellor, Andrew L.; Munn, David H.; Manicassamy, Santhakumar.

In: Cancer Research, Vol. 75, No. 4, 15.02.2015, p. 656-665.

Research output: Contribution to journalArticle

Hong, Y, Manoharan, I, Suryawanshi, A, Majumdar, T, Angus-Hill, ML, Koni, PA, Manicassamy, B, Mellor, AL, Munn, DH & Manicassamy, S 2015, 'β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin a metabolism in dendritic cells', Cancer Research, vol. 75, no. 4, pp. 656-665. https://doi.org/10.1158/0008-5472.CAN-14-2377
Hong, Yuan ; Manoharan, Indumathi ; Suryawanshi, Amol ; Majumdar, Tanmay ; Angus-Hill, Melinda L. ; Koni, Pandelakis A. ; Manicassamy, Balaji ; Mellor, Andrew L. ; Munn, David H. ; Manicassamy, Santhakumar. / β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin a metabolism in dendritic cells. In: Cancer Research. 2015 ; Vol. 75, No. 4. pp. 656-665.
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