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

Lookup NU author(s): Emeritus Professor Andrew MellorORCiD


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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.

Publication metadata

Author(s): Hong Y, Manoharan I, Suryawanshi A, Majunder T, Angus-Hill A, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2015

Volume: 75

Issue: 4

Pages: 656-665

Print publication date: 15/02/2015

Online publication date: 07/01/2015

Acceptance date: 26/11/2014

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research


DOI: 10.1158/0008-5472.CAN-14-2377

PubMed id: 25568183


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