Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer research (Chicago, Ill.), 2015-02, Vol.75 (4), p.656-665

Ort / Verlag

United States

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.