T-helper-1-cell cytokines drive cancer into senescence
T-helper-1-cell cytokines drive cancer into senescence
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DOI：
10.1038/nature11824
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发表时间：
2013-02-21
期刊：
影响因子：
64.8
通讯作者：
Roecken, Martin
中科院分区：
文献类型：
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作者：
Braumueller, Heidi;Wieder, Thomas;Roecken, Martin
通过适应性免疫控制癌症涉及许多明确的死亡（1-8）和清除（9-11）机制。然而，T 细胞和干扰素-γ (IFN-gamma) 有效抑制指数级癌症生长需要额外的未明确机制来阻止癌细胞增殖 (1-5,12,13)。在这里，我们表明，T 辅助细胞 1 细胞细胞因子 IFN-γ 和肿瘤坏死因子 (TNF) 的联合作用可直接诱导癌症的永久性生长停滞。为了安全地区分肿瘤免疫诱导的衰老与癌基因诱导的衰老 (9-11,14-17)，我们使用了小鼠模型，其中在大鼠胰岛素启动子控制下表达的猿猴病毒 40 大 T 抗原 (Tag) 通过减弱 p53 和 Rb 介导的细胞周期控制来产生肿瘤 (18,19)。当组合时，IFN-gamma 和 TNF 通过诱导 G1/G0 永久生长停滞、p16INK4a（也称为 CDKN2A）激活以及下游 Rb 丝氨酸 795 低磷酸化，驱动表达 Tag 的癌症进入衰老。除了 p16INK4a 之外，这种细胞因子诱导的衰老严格需要 STAT1 和 TNFR1（也称为 TNFRSF1A）信号传导。在体内，Tag 特异性 T 辅助细胞 1 细胞通过诱导 IFN-γ 和 TNFR1 依赖性衰老来永久阻止表达 Tag 的癌症。相反，即使在表达 TNFR1 的宿主中，表达 Tnfr1(-/-) 标签的癌症也能抵抗细胞因子诱导的衰老并快速生长。最后，由于 IFN-γ 和 TNF 在许多小鼠和人类癌症中诱导衰老，这可能是阻止癌症进展的一般机制。
Cancer control by adaptive immunity involves a number of defined death(1-8) and clearance(9-11) mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-gamma (IFN-gamma) requires additional undefined mechanisms that arrest cancer cell proliferation(1-5,12,13). Here we show that the combined action of the T-helper-1-cell cytokines IFN-gamma and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence(9-11,14-17), we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control(18,19). When combined, IFN-gamma and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-gamma- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-) Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-gamma and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.