Immune Suppression and Resistance Mediated by Constitutive Activation of Wnt/β-Catenin Signaling in Human Melanoma Cells
Immune Suppression and Resistance Mediated by Constitutive Activation of Wnt/β-Catenin Signaling in Human Melanoma Cells
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DOI：
10.4049/jimmunol.1102282
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发表时间：
2012-09-01
影响因子：
4.4
通讯作者：
Kawakami, Yutaka
中科院分区：
文献类型：
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作者：
Yaguchi, Tomonori;Goto, Yasufumi;Kawakami, Yutaka
肿瘤诱导的免疫抑制是降低免疫治疗抗肿瘤效果的主要问题，但其分子机制尚不清楚。我们评估了激活的Wnt/ β -连环蛋白通路在人黑色素瘤树突状细胞（dc）和ctl中的免疫抑制作用。IL-10的表达与β -catenin在人黑色素瘤细胞系和组织中的积累有关，并通过β -catenin/TCF直接结合IL-10启动子诱导。β -连环蛋白积累的黑色素瘤培养上清液具有损害DC成熟和诱导可能的调节性DC的活性。这些免疫抑制培养上清活性通过敲除黑色素瘤细胞中的β -连环蛋白而降低，部分原因是IL-10的下调。裸鼠脾和肿瘤浸润dc植入人突变β -catenin-过表达的黑色素瘤细胞后，其激活T细胞的能力低于来自对照黑色素瘤细胞小鼠的dc，这表明在人黑色素瘤中，激活Wnt/ β -catenin信号可以抑制dc。这种体内DC抑制可通过β -连环蛋白抑制剂PKF115-584恢复。β -连环蛋白过表达的黑色素瘤以不依赖il -10的方式抑制黑色素瘤特异性CTL产生ifn - γ，并且在体外和体内对CTL裂解更具抗性。这些结果表明，人类黑色素瘤中Wnt/ β -catenin通路可能部分通过IL-10的产生参与抗肿瘤免疫反应诱导和效应阶段的免疫抑制和免疫抵抗，它们可能是恢复Wnt/ β -catenin激活的黑色素瘤患者免疫能力的有吸引力的靶点。中国生物医学工程学报，2012,33(2):391 - 391。
Cancer-induced immunosuppression is a major problem reducing antitumor effects of immunotherapies, but its molecular mechanism has not been well understood. We evaluated immunosuppressive roles of activated Wnt/beta-catenin pathways in human melanoma for dendritic cells (DCs) and CTLs. IL-10 expression was associated with beta-catenin accumulation in human melanoma cell lines and tissues and was induced by direct beta-catenin/TCF binding to the IL-10 promoter. Culture supernatants from beta-catenin-accumulated melanoma have activities to impair DC maturation and to induce possible regulatory DCs. Those immunosuppressive culture supernatant activities were reduced by knocking down beta-catenin in melanoma cells, partly owing to downregulation of IL-10. Murine splenic and tumor-infiltrating DCs obtained from nude mice implanted with human mutant beta-catenin-overexpressed melanoma cells had less ability to activate T cells than did DCs from mice with control melanoma cells, showing in vivo suppression of DCs by activated Wnt/beta-catenin signaling in human melanoma. This in vivo DC suppression was restored by the administration of a beta-catenin inhibitor, PKF115-584. beta-catenin-overexpressed melanoma inhibited IFN-gamma production by melanoma-specific CTLs in an IL-10-independent manner and is more resistant to CTL lysis in vitro and in vivo. These results indicate that Wnt/beta-catenin pathways in human melanoma may be involved in immunosuppression and immunoresistance in both induction and effector phases of antitumor immunoresponses partly through IL-10 production, and they may be attractive targets for restoring immunocompetence in patients with Wnt/beta-catenin-activated melanoma. The Journal of Immunology, 2012, 189: 2110-2117.