β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells.
β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells.
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DOI：
10.1158/0008-5472.can-14-2377
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发表时间：
2015-02-15
期刊：
影响因子：
11.2
通讯作者：
Manicassamy S
中科院分区：
文献类型：
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作者：
Hong Y;Manoharan I;Suryawanshi A;Majumdar T;Angus-Hill ML;Koni PA;Manicassamy B;Mellor AL;Munn DH;Manicassamy S
肿瘤主动抑制抗肿瘤免疫，为成功的癌症免疫治疗创造了巨大的障碍。肿瘤诱导免疫耐受的分子机制在很大程度上是未知的。在本研究中，我们发现肿瘤微环境（TME）中的树突状细胞（dc）获得代谢维生素A产生维甲酸（RA）的能力，从而驱动T调节反应和免疫耐受。在树突状细胞中，耐受性反应依赖于通过β-catenin/T细胞因子（TCF）途径诱导的维生素a代谢酶。与这一观察结果一致，小鼠dc特异性缺失β-catenin显著降低T调节反应并延迟黑色素瘤生长。体内对维生素A代谢酶或β-catenin/TCF4通路的药理抑制对肿瘤生长和T调节反应的影响相似。因此，β-catenin/TCF4信号通过RA通路诱导局部调节性DC和调节性T细胞表型，确定该通路为抗癌免疫治疗的重要靶点。
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 (DCs) in the tumor microenvironment (TME) acquire the ability to metabolize vitamin A to produce retinoic acid (RA), which drives T regulatory 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 T regulatory responses and delayed melanoma growth. Pharmacological inhibition of either vitamin A metabolizing enzymes or the β-catenin/TCF4 pathway in vivo had similar effects on tumor growth and T regulatory 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.