期刊
CANCER RESEARCH
卷 75, 期 4, 页码 656-665出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-2377
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类别
资金
- NIH [DK097271, AI04875]
- GRU Cancer Center Seed Grant
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 beta-catenin/T-cell factor (TCF) pathway in DCs. Consistent with this observation, DC-specific deletion of beta-catenin in mice markedly reduced regulatory T-cell responses and delayed melanoma growth. Pharmacologic inhibition of either vitamin A-metabolizing enzymes or the beta-catenin/TCF4 pathway in vivo had similar effects on tumor growth and regulatory T-cell responses. Hence, beta-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. (C)2015 AACR.
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