TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment
TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment
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TERT 激活内源性逆转录病毒以促进免疫抑制肿瘤微环境
DOI：
10.15252/embr.202152984
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发表时间：
2022-02-02
期刊：
影响因子：
7.7
通讯作者：
Cong, Yu-Sheng
中科院分区：
文献类型：
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作者：
Mao, Jian;Zhang, Qian;Cong, Yu-Sheng
端粒酶通过端粒依赖性和端粒非依赖性的活性在肿瘤发生中起着关键作用，但其机制尚不完全清楚。使用单样本基因集富集分析（ssGSEA）在9,264肿瘤样本，我们观察到端粒酶逆转录酶（TERT）的表达与免疫抑制信号密切相关。我们证明，TERT可以激活内源性逆转录病毒（ERVs）的一个亚类，独立于其端粒酶活性，形成双链RNA（dsRNA），这是由RIG-1/MDA 5-MAVS信号通路感应，并触发干扰素信号在癌细胞中。此外，我们发现，TERT诱导的ERV/干扰素信号刺激趋化因子的表达，包括CXCL 10，这诱导了抑制性T细胞群的浸润，增加了CD 4（+）和FOXP 3（+）细胞的百分比。这些数据揭示了端粒酶作为ERV的转录激活因子的意外作用，并提供了有力的证据表明，端粒酶介导的ERV/干扰素信号有助于肿瘤中的免疫抑制。
Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observe that expression of telomerase reverse transcriptase (TERT) is closely associated with immunosuppressive signatures. We demonstrate that TERT can activate a subclass of endogenous retroviruses (ERVs) independent of its telomerase activity to form double-stranded RNAs (dsRNAs), which are sensed by the RIG-1/MDA5-MAVS signalling pathway and trigger interferon signalling in cancer cells. Furthermore, we show that TERT-induced ERV/interferon signalling stimulates the expression of chemokines, including CXCL10, which induces the infiltration of suppressive T-cell populations with increased percentage of CD4(+) and FOXP3(+) cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERV/interferon signalling contributes to immune suppression in tumours.