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

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.