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
Cancer Immunology, Inflammation, and Tolerance Program, GRU Cancer Center, Georgia Regents University, Augusta, Georgia, USA.
Hunstman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Cancer Res. 2015 Feb 15;75(4):656-665. doi: 10.1158/0008-5472.CAN-14-2377. Epub 2015 Jan 7.
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.
肿瘤会积极抑制抗肿瘤免疫，给成功的癌症免疫治疗造成巨大障碍。肿瘤诱导免疫耐受的分子机制在很大程度上尚不清楚。在本研究中，我们发现肿瘤微环境中的树突状细胞（DC）获得了代谢维生素A以产生视黄酸（RA）的能力，而视黄酸会驱动调节性T细胞反应和免疫耐受。耐受性反应依赖于通过DC中的β-连环蛋白/T细胞因子（TCF）途径诱导维生素A代谢酶。与这一观察结果一致，小鼠中DC特异性缺失β-连环蛋白显著降低了调节性T细胞反应，并延缓了黑色素瘤的生长。体内对维生素A代谢酶或β-连环蛋白/TCF4途径的药理学抑制对肿瘤生长和调节性T细胞反应有类似影响。因此，β-连环蛋白/TCF4信号通过RA途径诱导局部调节性DC和调节性T细胞表型，确定该途径为抗癌免疫治疗的重要靶点。
