TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis
TNFR1 signaling and IFN-γ signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis
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DOI：
10.1016/j.ccr.2008.04.001
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发表时间：
2008-06-01
期刊：
影响因子：
50.3
通讯作者：
Roecken, Martin
中科院分区：
文献类型：
--
作者：
Mueller-Hermelink, Nele;Braumueller, Heidi;Roecken, Martin
免疫反应可能通过诱导肿瘤休眠来阻止肿瘤生长。适应性免疫导致肿瘤休眠或促进多阶段癌变的机制尚不清楚。通过分析T抗原（Tag）诱导的胰岛多阶段癌变，我们发现Tag特异性CD4(+) T细胞选择性地进入胰岛周围的肿瘤微环境，在那里它们阻止或促进发育不良的胰岛向胰岛癌的转变。通过联合TNFR1信号和ifn - γ信号，tag特异性CD4(+) T细胞诱导抗血管生成趋化因子，阻止α (v) β(3)整合素表达、肿瘤血管生成、肿瘤细胞增殖和多阶段癌变，而不破坏表达tag的胰岛细胞。在缺乏TNFR1信号或ifn - γ信号的情况下，相同的T细胞矛盾地促进血管生成和多阶段癌的发生。因此，肿瘤特异性T细胞可以通过细胞因子信号直接检测多阶段癌变。
Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4(+) T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-gamma signaling, Tag-specific CD4(+) T cells induce antiangiogenic chemokines and prevent alpha(v)beta(3) integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-gamma signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling.